QSAR validation.

Validity of the generated QSAR models (2 and 3) was confirmed by Leave-one-out (LOO) internal validation (r2 = 0.809 and 0.915,
respectively). Cross-validation was also employed where q2, which is equivalent to r2 (pred), were 0.619 and 0.672, respectively. As value of q 2 increased over
than 0.5, indi-cating the validity of a QSAR model. In addition, validation was employed by measuring the residuals between the experimental and the predicted
activities of the training set (Table 11). Interest-ingly, the predicted activities by the established QSAR models were very close to those experimentally assessed,
indicating that these models could be applied for prediction of more effective hits hav-ing the same skeletal framework.
Finally, depending on the generated QSAR models (2 and 3), the PPAR c binding affinity and insulin-secreting ability were computa-tionally determined for
the in vitro untested new compounds (19e, 25b, 25e, 25h and 25i) (Table 12).

2.3.4. In silico ADMET analysis

Discovery studio 2.5 was used to predict ADMET (absorption, distribution, metabolism, excretion and toxicity) for both the designed compounds and the
reference drugs (rosiglitazone and glimiperide). Predicted ADMET for all the tested compounds are listed in Table 13.

It was found that BBB penetration of the designed compounds is expected to be very low. So that, all compounds were expected to be safe to CNS. Moreover,
most of the designed compounds were expected to possess good human intestinal absorption. Addition-ally, the CYP2D6 score predicts the inhibitory and non-
inhibitory behavior of particular compound on Cytochrome P450 2D6 enzyme. All the synthesized members are predicted as non-inhibi-tors of CYP2D6. Hence
the side effects (i.e., liver dysfunction) are not expected upon administration of these compounds. Addition-ally, the closer the hepatotoxicity scores to one, the
more probabil-ity to be toxic, while the closer the hepatotoxicity scores to zero, the more probability to be nontoxic. The compounds involves cyclohexyl moiety
were found to have hepatotoxicity probability values of the compounds with cyclohexyl moiety lie in the range of 0.2050.291. Hence these derivatives are likely
to be non-hepa-totoxic. While the compounds with n-butyl and phenyl have hep-atotoxicity probability values ranging from 0.543 to 0.907. This indicates that
these derivatives are likely to possess hepatotoxicity. The plasma protein binding model predicts the binding ability of a compound to plasma proteins. Most of
the synthesized compounds have PPB level equal to one. Hence there is high probability that these compounds can reach the desired targets. It is well known that
numerous drug candidates have failed during clinical tests because of problems related to their absorption properties. Up on computational investigation of the
synthesized compound, it was found that ADME aqueous solubility logarithmic level of most compounds equal 3 or 2 which indicates good to moderate aque-ous
solubility.

2.4. Structure activity relationship (SAR)

As outlined in the rationale, we aimed at studying the SAR of quinazoline-4(3H)-one-sulfonylurea hybrids as potential anti-hyperglycemic agents targeting
both PPARc and SUR. Observing the results of different biological experiments we could deduce valuable data about the structure activity relationships.
At first, we explored the effect of the different sulfonylurea derivatives on the in vivo anti-hyperglycemic activity. The % reduc-tion in blood glucose levels of
compounds 19a, 19d, 25a and 25g incorporating cyclohexyl moiety were found to be higher than that of corresponding members 19c, 19f 25c and 25i
incorporating n-butyl group, and the later were found to be more active than that with phenyl substitution as compounds 19b, 19e, 25b and 25h, indi-cating that
alicyclic (cyclohexyl) derivatives are more advanta-geous than open chain aliphatic (n-butyl) ones, and also, the aliphatic substitutions are more preferable than
aromatic ones. At the same time, it was found that aliphatic substitutions are more active than aromatic ones against SUR. On the other hand, it was found that
phenyl substitutions are more active than alipha-tic ones against PPARc.

The increased % reduction in blood glucose levels of compounds

19af, than those of their corresponding members 25aI, indicated that sulfonylurea substitution on 2-position of quinazoline-4 (3H)-one moiety is better than
that on 3-position. At the same time, this indicated that four atoms linker is superior to three atoms one.

We then examined the effect of the substitution on the pendant phenyl ring at 3-position of quinazoline-4(3H)-one moiety. The activities of compounds with
para-methoxy substitution (19ac) were better than that of para-methyl substituted analogs (19df), indicating that grafting a methoxy group, at the 4-positions is
ben-eficial for the activity.

3. Conclusion

In the present work, a series of novel quinazolin-4(3H)-one derivatives bearing sulfonylurea moieties have been designed, syn-thesized and characterized.
These compounds were screened for
their in vivo anti-hyperglycemic activity against STZ-induced hyperglycemic rats. The results indicate that compounds 19a, 19d, 19f and 25g have promising
anti-hyperglycemic activities. In order to strengthen the in vivo screening, the most active com-pounds were further evaluated for their in vitro PPAR c binding
affinity and insulin-secreting ability. Compounds 19b, 19d, 19f, 25f and 25g exhibited significant PPARc binding affinity, while compounds 19d, 19f, and 25d
showed powerful insulin-secreting ability. The docking and pharmacophore studies were performed, which demonstrate that compounds 19d, 25e, 25f and 25g
have sig-nificant dock scores and binding affinity towards PPAR c. While compounds 19a, 19c, 19f, 25d and 25i showed high fit values toward the generated
pharmacophore model. In addition, the gen-erated QSAR models, performed to explore the structural require-ments controlling the observed affinity of the tested
compounds toward PPARc and SUR, hinted that the PPARc binding affinity was affected by partition coefficient (Alog P), molar refractivity (MR), molecular
polar surface area (MPSA) and jurs descriptors (PPSA1 and WPSA1), while the insulin-secreting ability was affected by molar refractivity (MR), number of
hydrogen bond donors (HBD), first order molecular connectivity index (CHI-1), jurs descriptors (PPSA-1 and WPSA-2) and length of molecule in the y
dimension (Shad-Y). Here, it has been demonstrated that the utility of this chemistry may lead to important PPARc and SUR agonist molecules, and will also
require further studies to design more specific and efficient molecules. Based on the QSAR information, the lipophilicity of the synthesized compounds should be
increased to enhance PPARc binding affinity.

4. Materials and methods

4.1. Chemistry

4.1.1. General
melting points of the synthesized compounds were measured on a Gallenkamp melting point apparatus. The IR spectra were car-ried out using a Pye-Unicam
SP-3300 infrared spectrophotometer (KBr dicks) and expressed in wave number (cm 1).1H NMR spectra were run at 400 MHz, on a Varian Mercury VX-300
and Bruker Avance III NMR spectrometer respectively, while 13C NMR spectra were run at 75 MHz. TMS was used as an internal standard in deuterated
dimethylsulphoxide (DMSO-d6). Chemical shifts (d) are quoted in ppm. The abbreviations used are as follows: s, sin-glet; d, doublet; m, multiplet. All coupling
constant (J) values are given in hertz. The mass spectra were recorded on Shi-madzuGCMS-QP-1000EX mass spectrometer at 70 eV. Elemental analyses were
performed on CHN analyzer and all compounds were within 0.4 of the theoretical values. The reactions were monitored by thin-layer chromatography (TLC)
using TLC sheets coated with UV fluorescent silica gel Merck 60 F254 plates and were visualized using UV lamp and different solvents as mobile phases. All
reagents and solvents were purified and dried by stan-

dard techniques. All the newly synthesized compounds gave satis-factory elemental analysis. Compounds 15a,b, 16a,b,17, 21ac, 22ac, 23ac are previously
reported.
 M.K. Ibrahim et al. / Bioorganic & Medicinal Chemistry 25 (2017) 47234744 4739

4. Materials and methods

4.1. Chemistry

4.1.1. General
melting points of the synthesized compounds were measured on a Gallenkamp melting point apparatus. The IR spectra were car-ried out using a Pye-Unicam
SP-3300 infrared spectrophotometer (KBr dicks) and expressed in wave number (cm 1).1H NMR spectra were run at 400 MHz, on a Varian Mercury VX-300
and Bruker Avance III NMR spectrometer respectively, while 13C NMR spectra were run at 75 MHz. TMS was used as an internal standard in deuterated
dimethylsulphoxide (DMSO-d6). Chemical shifts (d) are quoted in ppm. The abbreviations used are as follows: s, sin-glet; d, doublet; m, multiplet. All coupling
constant (J) values are given in hertz. The mass spectra were recorded on Shi-madzuGCMS-QP-1000EX mass spectrometer at 70 eV. Elemental analyses were
performed on CHN analyzer and all compounds were within 0.4 of the theoretical values. The reactions were monitored by thin-layer chromatography (TLC)
using TLC sheets coated with UV fluorescent silica gel Merck 60 F254 plates and were visualized using UV lamp and different solvents as mobile phases. All
reagents and solvents were purified and dried by stan-

dard techniques. All the newly synthesized compounds gave satis-factory elemental analysis. Compounds 15a,b, 16a,b,55,56 17,38 21ac, 22ac, 23ac5760 are
previously reported.

4.1.2. General procedure for synthesis of compounds (18a,b)

A mixture of potassium salt of 3-(4-methylphenyl)-2-sul-fanylquinazolin-4(3H)-one 16a, (13.35g, 0.05 mol) or 3-(4-methox-yphenyl)-2-sulfanylquinazolin-
4(3H)-one 16b, (14.15 g, 0.05 mol) and 2-chloro-N-(4-sulfamoylphenyl)acetamide 17, (12.4 g, 0.05 mol) in dry DMF (50 mL) was heated over a water bath for
12 h. After cooling to room temperature, the reaction mixture was poured on ice cold water (500 mL) with continuous stirring. The produced white precipitated
was filtered, washed with water and hot ethanol to afford compounds 18a,b, respectively.

4.1.2.1. 2-{[3-(4-Methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-sulfanyl}-N-(4-sulfamoylphenyl)acetamide (18a). White powder (yield 70%); m.p. 236238

LC; IR (KBr, cm 1): 3352 (NH), 3281, 3212 (NH2), 3040 (CH aromatic), 1680 (C@O), 1325, 1154 (SO2); 1H NMR (DMSO-d6) d ppm: 2.42 (s, 3H, CH3), 4.09
(s, 2H, CH2), 7.31 (s, 2H, NH2, D2O exchangeable),7.367.42 (m, 4H, Ar-H),
7.44 (d, J = 8.2 Hz, 1H, Ar-H), 7.53 (d, J = 8.2 Hz, 1H, Ar-H), 7.78
7.85 (m, 5H, Ar-H), 8.07 (d, J = 8.2 Hz, 1H, Ar-H), 10.69 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6, 100 MHz) d (ppm): 21.4, 37.4, 118.6(2),
125.7, 126.3(2), 128.7(2), 129.4(2), 133.1, 138.3, 141.4, 146.9, 147.6, 156.8, 160.5, 166.3; DEPT (DMSO-d6, 100 MHz) d (ppm): 21.4(1CH3), 37.4(1CH2),
118.6(2), 126.3,
126.5, 127.1, 127.3(2), 129.4(2), 130.5(2), 135.3(12CH); Mass:
480 (M+, 1.32%), 299 (41.38%), 262 (33.48%), 233 (73.83%), 217
(43.88%), 95 (100% base beak); Anal. Calcd. For C 23H20N4O4S2
(480.09): C, 57.49; H, 4.20; N, 11.66; Found: C, 57.73; H, 4.29; N,
11.87%.

4.1.2.2. 2-{[3-(4-Methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-sulfanyl}-N-(4-sulfamoylphenyl)acetamide (18b). Gray powder (yield 73%); m.p. 217219

LC; IR (KBr, cm 1): 3353 (NH), 3283, 3218 (NH2), 3045 (CH aromatic), 2959 (CH aliphatic), 1675 (C@O), 1324, 1158 (SO2); 1H NMR (DMSO-d6) d ppm:
3.85 (s, 3H, OCH3), 4.11 (s, 2H, CH2), 6.85 (d, J = 5.2 Hz, 1H, Ar-H), 6.90 (d, J = 5.2 Hz, 1H, Ar-H), 7.05 (d, J = 5.2 Hz, 1H, Ar-H), 7.13 (s, 1H, Ar-H), 7.32
7.59 (m, 5H, Ar-H), 7.82 (s, 2H, NH2, D2O exchangeable), 8.08 (s, 1H, Ar-H), 10.67 (s, 1H, NH, D2O exchangeable); 13C NMR
(DMSO-d6, 100 MHz) d (ppm): 39.9, 55.6, 115.1(2), 118.7(2), 122.1, 127.3, 129.5(2), 131.1(2), 138.1, 140.6, 141.8, 147.1, 156.0,
157.2, 159.1, 160.6; Mass: 496 (M+, 1.84%), 377 (29.10%), 252 (61.66%), 228 (76.59%), 178 (84.44%), 125 (100% base beak); Anal. Calcd. For
C23H20N4O5S2 (496.09): C, 55.63; H, 4.06; N, 11.28; Found: C, 55.91; H, 4.11; N, 11.41%.

4.1.3. General procedure for synthesis of compounds (19a,f)

A mixture of 2-{[3-(4-methylphenyl)-4-oxo-3,4-dihydroquina-zolin-2-yl]sulfanyl}-N-(4-sulfamoylphenyl)acetamide 18a, (4.8 g, 0.01 mol) or 2-{[3-(4-
methoxyphenyl)-4-oxo-3,4-dihydroquina-zolin-2-yl]sulfanyl}-N-(4-sulfamoylphenyl) acetamide 18b (4.96 g, 0.01 mol) and anhydrous potassium carbonate (0.02
mol 2.76 g) in dry acetone (350 ml) were refluxed with stirring for about 1.5 h. Then, the reaction mixture was cooled, with subsequent addition of appropriate
isocyanates namely, cyclohexyl isocyanate, phenyl isocyanate and butyl isocyanate. Next, the reaction mixture was refluxed with stirring for additional 16 h. after
the completion of the reaction, acetone was removed by evaporation under reduced pressure. Then, 750 ml of water was added to dissolve the resulting residue.
Acidification of the solution with 6 N aque-ous hydrochloric acid caused the precipitation of the product which was collected by filtration and crystallized from
90% aque-ous ethanol to yield purified sulfonylurea derivatives 19af, respectively.

4.1.3.1. 2-{[3-(4-Methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-sulfanyl}-N-{4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenyl}acetamide (19a). White powder

(yield 80%); m.p. 213215 LC; IR(KBr, cm 1): 3348, 3117 (NH, NH), 2929 (CH aliphatic), 1681 (C@O), 1322, 1158 (SO2); 1H NMR (DMSO-d6) d ppm: 0.97
1.60 (m, 10H, cyclohexyl group), 2.42 (s, 3H, CH3), 3.32 (m, 1H, of cyclohexyl group), 4.07 (s, 2H, S-CH2), 6.30 (s, 1H, NH-cyclohexyl, D2O exchangeable),
7.177.41 (m, 5H, Ar-H), 7.50 (d, J = 8 Hz, 1H, Ar-H), 7.677.84 (m, 5H, Ar-H), 8.06 (d, J = 8 Hz, 1H, Ar-H), 10.25 (s, 1H, CH2-CONHPhenyl, D2O
exchangeable), 10.77 (s, 1H, SO2NH, D2O exchangeable); Anal. Calcd. For C30H31N5O5S2 (605.18): C, 59.49; H, 5.16; N, 11.56; Found: C, 59.78; H, 5.24; N,
11.73 %.

4.1.3.2. 2-{[3-(4-Methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-
sulfanyl}-N-{4-[N-(phenylcarbamoyl)sulfamoyl]phenyl}acetamide
(19b). Brown precipitate (yield 66%); m.p. 183185 LC; IR (KBr,
cm 1): 3467, 3312 (2NH), 3060 (CH aromatic), 1674 (C@O), 1308,
1155 (SO2); 1H NMR (DMSO-d6) d ppm: 2.42 (s, 3H, CH3), 4.08 (s,
2H, S-CH2), 7.138.07 (m, 17H, Ar-H), 8.67 (s, 1H, NH-Phenyl,
D2O exchangeable), 10.66 (s, 1H, CH2CONH-Phenyl, D2O exchange-
able), 10.87 (s, 1H, SO2NH, D2O exchangeable); Anal. Calcd. For C30-
H25N5O5S2 (605.18): C, 60.09; H, 4.20; N, 11.68; Found: C, 60.41; H,
4.18; N, 11.85 %.

4.1.3.3. 2-{[3-(4-Methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-
sulfanyl}-N-{4-[N-(butylcarbamoyl)sulfamoyl]phenyl}acetamide
(19c). Off white crystals (yield 55%); m.p. 172174 LC; IR(KBr,
cm 1): 3307 (NH), 2945 (CH aliphatic), 1684 (C@O), 1325, 1155 (SO2); 1H NMR (DMSO-d6) d ppm: 0.86 (t, 3H, CH2-CH3), 1.23 1.28 (m, 2H, CH2-CH3),
1.391.44 (m, 2H, CH2-CH2-CH3), 2.42 (s, 3H, CH3-Phenyl), 2.943.08 (t, 2H, CH2-CH2-CH2-CH3), 4.09 (s, 2H, S-CH2), 6.46 (s, 1H, NH-butyl, D2O
exchangeable), 7.18 (d, J = 8 Hz, 1H, Ar-H), 7.26738 (m, 3H, Ar-H), 7.52 (d, J = 8 Hz, 1H, Ar-H), 7.777.95 (m, 6H, Ar-H), 8.06 (d, J = 8 Hz, 1H, Ar-H), 10.80
(s, 1H, CH2CONH-Phenyl, D2O exchangeable), 11.58 (s, 1H, SO2NH, D2O exchangeable); 13C NMR (DMSO-d6, 100 MHz) d (ppm): 14.3, 19.9, 21.4, 31.6,
39.7, 42.1, 119.1(2), 119.8, 127.0(2), 129.2(2), 130.5(2), 133.2, 139.6, 142.5, 149.4, 156.3, 157.5, 160.9, 167.1;
4740 M.K. Ibrahim et al. / Bioorganic & Medicinal Chemistry 25 (2017) 47234744

DEPT (DMSO-d6, 100 MHz) d (ppm): 14.3(1CH3), 19.9(1CH2), 21.4 (1CH3), 31.6(1CH2), 39.7(1CH2), 41.1(1CH2), 119.8(2), 122.7, 126.3, 127.3, 128.9(2),
129.3(2), 130.5(2), 135.3(12CH); Anal. Calcd. For C 28H29N5O5S2 (579.16): C, 58.02; H, 5.04; N, 12.08; Found: C, 58.24; H, 5.12; N, 12.34 %.

4.1.3.4. 2-{[3-(4-Methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-sulfanyl}-N-{4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenyl}acetamide (19d).Yellow

powder (yield 77%); m.p. 196198 LC; IR(KBr, cm 1): 3357, 3250 (NH, NH), 3097 (CH aromatic), 2928 (CH aliphatic), 1680 (C@O), 1330, 1165 (SO2); 1H
NMR (DMSO-d6) d ppm: 1.05 1.64 (m, 10H, cyclohexyl group), 3.22 (m, 1H, of cyclohexyl group),
3.85 (s, 3H, OCH3) 4.08 (s, 2H, S-CH2), 6.30 (s, 1H, NH-cyclohexyl, D2O exchangeable), 7.12 (d, J = 8 Hz, 2H, Ar-H), 7.397.46 (m, 3H, Ar-H), 7.50 (d, J = 8
Hz, 1H, Ar-H),7.797.86 (m, 5H, Ar-H), 8.06 (d, J = 8 Hz, 1H, Ar-H), 10.25 (s, 1H, CH2CONH-Phenyl, D2O exchangeable), 10.79 (s, 1H, SO2NH, D2O
exchangeable); 13C NMR (DMSO-d6, 100 MHz) d (ppm): 24.3, 25.4, 32.5, 39.9, 48.5, 56.0, 114.7(2), 119.1(2), 119.9, 126.1, 127.1(2), 128.3, 128.9(2), 130.4,
134.4, 135.4, 143.1, 147.6, 157.5, 160.0, 161.2, 167.1; DEPT (DMSO-d6, 100 MHz) d (ppm): 24.3(2CH2), 25.4(1CH2), 37.7 (1CH2), 37.6(2CH2), 48.5(1CH),
55.8(1CH3), 115.1(2), 119.1(2), 126.1, 126.3, 127.1(2), 129.3(2), 131.2, 135,1(13CH); Anal. Calcd. For C30H31N5O6S2 (605.18): C, 57.96; H, 5.03; N, 11.26;
Found: C, 58.08; H, 5.12; N, 11.39 %.

4.1.3.5. 2-{[3-(4-Methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-
sulfanyl}-N-{4-[N-(phenylcarbamoyl)sulfamoyl]phenyl}acetamide
(19e). Brown powder (yield 60%); m.p. 201203 LC; IR (KBr, cm 1):
3329, 3219 (2NH), 3066 (CH aromatic), 2922 (CH aliphatic), 1663
(C@O), 1338, 1160 (SO2); 1H NMR (DMSO-d6) d ppm: 3.85 (s, 3H,
OCH3), 4.08 (s, 2H, S-CH2), 8.80 (s, 1H, NH-Phenyl, D2O exchange-
able), 6.987.01 (dd, J = 8 & 4 Hz, 1H, Ar-H), 7.04 (d, J = 8 Hz, 2H,
Ar-H), 7.227.26 (dd, J = 8 & 8 Hz, 2H, Ar-H), 7.31 (d, J = 8 Hz, 2H,
Ar-H), 7.387.43 (m, 3H, Ar-H), 7.48 (d, J = 8 Hz, 1H, Ar-H), 7.73
7.78 (m, 1H, Ar-H), 7.82 (d, J = 8 Hz, 2H, Ar-H), 7.92 (d, 2H, Ar-H),
8.04 (d, J = 8 Hz, 1H, Ar-H), 10.46 (s, 1H, CH2CONH-Phenyl, D2O exchangeable), 10.81 (s, 1H, SO2NH, D2O exchangeable); 13C NMR (DMSO-d6, 100
MHz) d (ppm): 39.7, 55.9, 115.1(2), 119.0(2), 119.4(2), 120.0, 123.6, 126.4, 127.0(2), 128.5(2), 129.2(2), 131.0,
134.2, 135.3, 138.4, 143.6, 147.5, 149.7, 158.0, 160.5, 161.2,
167.2; DEPT (DMSO-d6, 100 MHz) d (ppm): 39.7(1CH2), 55.9 (1CH3), 115.1(2), 119.0(2), 119.4(2), 123.6, 126.3, 126.4(2), 127.0
(2), 129.2(2), 129.3, 131.0, 135.3(17CH); Anal. Calcd. For C30H25N5-O6S2 (615.12): C, 58.53; H, 4.09; N, 11.83; Found: C, 58.87; H, 4.12; N, 11.52%.

4.1.3.6. 2-{[3-(4-Methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-
sulfanyl}-N-{4-[N-(butylcarbamoyl)sulfamoyl]phenyl}acetamide
(19f). Yellow precipitate (yield 55%); m.p. 172174 LC; IR (KBr,
cm 1): 3292, 3107 (2NH), 2945 (CH aliphatic), 1681 (C@O), 1323,
1158 (SO2); 1H NMR (DMSO-d6) d ppm: 0.840.89 (t, 3H, CH2-
CH3), 1.231.30 (m, 2H, CH2-CH3), 1.361.53 (m, 2H, CH2-CH2-
CH3), 3.063.12 (t, 2H, CH2-CH2-CH2-CH3), 3.80 (s, 3H, OCH3),
4.10 (s, 2H, S-CH2), 6.48(s, 1H, NH-butyl, D2O exchangeable),
6.818.07 (m, 12H, Ar-H), 10.75 (s, 1H, CH2CONH-Phenyl, D2O exchangeable), 11.46 (s, 1H, SO2NH, D2O exchangeable); 13C NMR (DMSO-d6, 100 MHz) d
(ppm): 14.1, 19.8, 31.0, 31.6, 39.7, 55.7, 115.1(2), 119.1(2), 120.0, 126.3, 127.2, 128.7(2), 130.4(2), 130.9,
135.3, 147.5, 156.3, 158.0, 160.5, 160.6, 161.3, 162.8, 166.9; Anal. Calcd. For C 28H29N5O6S2 (595.16): C, 56.46; H, 4.91; N, 11.76; Found: C, 56.81; H, 4.97;
N, 11.94%.
4.1.4. General procedure for synthesis of compounds (24ac)
A mixture of potassium salt of 2-methyl-quinazolin-4(3H)-one 23a, (9.91 g, 0.05 mol), potassium salt of 2-ethyl-quinazolin-4 (3H)-one 23b, (10.61 g, 0.05
mol) or 6-bromo-2-methylquina-zolin-4(3H)-one 23c, (13.85 g, 0.05 mol) and 2-chloro-N-(4-sul-famoylphenyl)acetamide 17 (12.4 g, 0.05 mol) in dry DMF (50
mL) was heated over a water bath for 12 h. After cooling to room temperature, the reaction mixture was poured on ice-cold water (500 mL). The formed white
precipitated product was fil-tered, washed with water and hot ethanol to afford compounds 24ac, respectively.

4.1.4.1. 2-(2-Methyl-4-oxoquinazolin-3(4H)-yl)-N-(4-sulfamoylpheyl) acetamide (24a). White powder (yield 80%); m.p. 290292 LC; IR (KBr, cm 1): 3324,
3282 (NH2), 3083 (CH aromatic), 1678 (C@O), 1320, 1154 (SO2); 1H NMR (DMSO-d6) d ppm: 2.49 (s, 3H, CH3), 5.00 (s, 2H, CH2), 7.82 (s, 2H, NH2, D2O
exchangeable), 7.28 (dd, J = 8 & 4 Hz, 1H, Ar-H), 7.54 (d, J = 8 Hz, 1H, Ar-H), 7.7179 (m, 5H, Ar-H), 8.01 (d, J = 8 Hz, 1H, Ar-H), 10.74 (s, 1H, NH, D2O
exchangeable); 13C NMR (DMSO-d6, 100 MHz) d (ppm): 23.4, 47.7, 119.3(2), 120.0, 126.6, 126.8, 127.0, 127.3(2), 134.9, 139.1, 141.9, 147.5, 155.7, 161.6,
166.7; DEPT (DMSO-d6, 100 MHz) d (ppm): 23,4(1CH3), 47.7(1CH2), 119.3(2), 126.6, 126.8, 127.0, 127.3(2),129.2, 134.9(8CH); Mass: 372 (M +, 1.61%), 227
(17.95%),
171 (100% base beak), 155 (50.01%); Anal. Calcd. For C17H16N4O4S (372.40): C, 54.83; H, 4.33; N, 15.05; Found: C, 54.97; H, 4.38; N, 15.19%.

4.1.4.2. 2-(2-Ethyl-4-oxoquinazolin-3(4H)-yl)-N-(4-sulfamoylpheyl) acetamide (24b). White precipitate (yield 72%); m.p. 279281 LC; IR(KBr, cm 1):
3277(NH), 3068(CH aromatic), 1673(CO), 1323, 1160(SO2); 1H NMR (DMSO-d6) d ppm: 1.27 (t, 3H, CH3, J = 7.2 Hz), 2.822.83 (q, 2H, CH2-CH3, J = 7.2
Hz), 5.02 (s, 2H, CH2-CO), 7.27 (s, 2H, NH2, D2O exchangeable), 7.50 (d, J = 8 Hz, 1H, Ar-H),
7.65 (m, 6H, Ar-H), 8.08 (d, J = 8 Hz, 1H, Ar-H), 10.96 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6, 100 MHz) d (ppm): 10.9, 26.9, 48.3, 118.8(2),
120.6, 126.5, 126.7, 127.3(2), 133.4, 139.5, 142.9, 148.6, 156.2, 161.9, 166.8; DEPT (DMSO-d6, 100 MHz) d (ppm): 10.9(1CH3), 26.9(1CH2), 48.3(1CH2),
118.8(2), 126.5, 126.7, 127.3(2), 129.2, 133.4(8CH); Mass: 386 (M +, 3.98%), 297 (27.14%), 236 (50.30%), 123 (50.67%), 83 (100% base beak); Anal. Calcd.
For C18H18N4O4S (386.43): C, 55.95; H, 4.70; N, 14.50; Found: C, 56.09; H, 4.76; N, 14.78%

4.1.4.3. 2-(6-Bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(4-sul-famoylpheyl) acetamide (24c). White powder (yield 85%); m.p. 254256 LC; IR (KBr, cm 1):
3229 (NH), 3072 (CH aromatic), 1677 (C@O), 1317, 1152 (SO2); 1H NMR (DMSO-d6) d ppm: 2.55 (s, 3H, CH3), 5.00 (s, 2H, CH2), 7.58 (s, 2H, NH2, D2O
exchangeable), 7.608.42 (m, 7H, Ar-H), 10.81 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6, 100 MHz) d (ppm): 22.8, 48.2, 118.6(2), 121.3, 123.2,
124.6, 129.4(2), 131.1, 133.6, 137.9, 139.4, 143.6, 148.9,
161.8, 166.7; DEPT (DMSO-d6, 100 MHz) d (ppm): 22.8(1CH3),
48.2(1CH2), 118.6(2), 124.6, 129.4(2), 131.1, 133.6(7CH); Mass: 450 (M +, 1.06%), 452 (M+2, 1.03%), 280(100% base beak), 266 (69.17%), 236 (64.89%), 222
(34.46%); Anal. Calcd. For C17H15BrN4-O4S (450.30): C, 45.24; H, 3.35; N, 12.41; Found: C, 45.51; H, 3.34; N, 12.55%.

4.1.5. General procedure for synthesis of compounds (25ai)

A mixture of 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(4-sul-famoylpheyl) acetamide 24a (3.72 g, 0.01 mol.), 2-(2-ethyl-4-oxo-quinazolin-3(4H)-yl)-N-(4-
sulfamoylpheyl)acetamide 24b (3.86 g, 0.01 mol.) or 2-(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(4-sulfamoylpheyl) acetamide 24c (4.50 g, 0.01 mol.)
and (2.76 g,
 M.K. Ibrahim et al. / Bioorganic & Medicinal Chemistry 25 (2017) 47234744 4741

0.02 mol.) of anhydrous potassium carbonate in 350 mL of dry ace-tone was refluxed with stirring for about 1.5 h. After cooling, appropriate isocyanates namely
cyclohexyl isocyanate, phenyl iso-cyanate and butyl isocyanate (0.01 mol.) was added dropwise to reaction mixture. Then, the reaction mixture was refluxed with
continuous stirring for additional 16 h. Up on completion of the reaction, acetone was removed by evaporation under reduced pressure to obtain solid cake. Water
(750 ml) was added to dis-solve the resulting residue with subsequent acidification with 6 N aqueous hydrochloric acid to produce white precipitate. The formed
precipitate was collected by filtration and crystallized from 90% aqueous ethanol to give the target sulfonylurea derivatives 25ai, respectively.

4.1.5.1. 2-(2-Methyl-4-oxoquinazolin-3(4H)-yl)-N-{4-[N(cyclohexyl-carbamoyl) sulfamoyl]phenyl}acetamide(25a). Yellow crystals (yield 70%); m.p. 296298

LC; IR (KBr, cm 1): 3350 (NH), 3062 (CH aro-matic), 2931(CH aliphatic), 1668 (C@O), 1338, 1165 (SO2); 1H NMR (DMSO-d6) d ppm: 1.081.62 (m, 10H,
cyclohexyl group), 2.55 (s, 3H, CH3), 3.23 (m, 1H, of cyclohexyl group), 5.00 (s, 2H, CH2), 6.23 (s, 1H, NH-cyclohexyl, D2O exchangeable), 7.47 (d, J = 7.5 Hz,
1H, Ar-H), 7.61 (d, J = 8.1 Hz, 1H, Ar-H), 7.77 (m, 5H, Ar-H), 8.08 (d, J = 7.5 Hz, 1H, Ar-H), 10.83 (s, 1H, NH-Phenyl, D2O exchangeable), 11.44 (s, 1H,
SO2NH, D2O exchangeable); Anal. Calcd. For C24H27N5O5S (497.17): C, 57.93; H, 5.47; N, 14.08; Found: C, 58.12; H, 5.33; N, 14.31%.

4.1.5.2. 2-(2-Methyl-4-oxoquinazolin-3(4H)-yl)-N-{4-[N(phenylcar-bamoyl)sulfamoyl] phenyl} acetamide (25b). Brown precipitate (yield 62%); m.p. 283285
LC; IR (KBr, cm 1): 3313 (NH), 3068 (CH aromatic), 1648 (C@O), 1311, 1160 (SO2); 1H NMR (DMSO-d6) d ppm: 2.56 (s, 3H, CH3), 5.00 (s, 2H, CH2), 6.94
8.10 (m, 13H, Ar-H), 8.68 (s, 1H, NH-Phenyl, D2O exchangeable), 10.72 (s, 1H, CH2CONH-Phenyl, D2O exchangeable), 10.95 (s, 1H, SO2NH, D2O
exchangeable); Anal. Calcd. For C24H21N5O5S (491.13): C, 58.65; H, 4.31; N, 14.25; Found: C, 58.91; H, 4.38; N, 14.51%.

4.1.5.3. 2-(2-Methyl-4-oxoquinazolin-3(4H)-yl)-N-{4-[N(butylcar-bamoyl)sulfamoyl]phenyl}acetamide (25c). Brown powder (yield 55%); m.p. 202204 LC; IR
(KBr, cm 1): 3335 (NH), 3060 (CH Aro-matic), 2951 (CH aliphatic), 1691 (C@O), 1325, 1159 (SO2); 1H NMR (DMSO-d6) d ppm: 0.87 (t, 3H, CH2-CH3),
1.221.27 (m, 2H, CH2-CH3), 1.331.42 (m, 2H, CH2-CH2-CH3), 2.69 (s, 3H, CH3-quina-zoline), 3.06 (t, 2H, CH2-CH2-CH2-CH3), 5.07 (s, 2H, CH2-CO), 7.28
(s, 1H, NH-butyl), 7.59 (d, J = 7.6 Hz, 1H, Ar-H), 7.76 8.22 (m, 11H, Ar-H), 8.23 (d, J = 5 Hz, 1H, Ar-H), 10.65 (s, 1H, CH2CONH-Phe-nyl, D2O
exchangeable), 11.21 (s, 1H, SO2NH, D2O exchangeable); 13C NMR (DMSO-d6, 100 MHz) d (ppm): 13.5, 20.1, 22.3, 32.1, 39.9, 48.1, 118.9(2), 123.2, 126.9,
127.1, 127.8, 129.3(2), 134.1, 136.3, 142.3, 144.1, 149.9, 157.3, 160.5, 166.7; DEPT (DMSO-d6,

100 MHz) d (ppm): 13.5(1CH3), 20.1(1CH2), 22.3(1CH3), 32.1 (1CH2), 39.9(1CH2), 48.1(1CH2), 118.9(2), 126.9, 127.1, 127.8, 129.3(2), 134.1(8CH); Anal.
Calcd. For C22H25N5O5S (471.16): C, 56.04; H, 5.34; N, 14.85; Found: C, 56.31; H, 5.40; N, 15.08%.

4.1.5.4. 2-(2-Ethyl-4-oxoquinazolin-3(4H)-yl)-N-{4-[N(cyclohexylcar-bamoyl)sulfamoyl]phenyl}acetamide (25d). White crystal (yield 65%); m.p. 183185 LC;
IR (KBr, cm 1): 3330 (NH), 3046 (CH aro-matic), 2929 (CH aliphatic), 1704 (C@O), 1318, 1160 (SO2); 1H NMR (DMSO-d6) d ppm: 0.85 (t, 3H, CH3), 0.97
1.72 (m, 10H, cyclo-hexyl group), 2.812.84 (q, 2H, CH2-CH3), 3.28 (m, 1H, of cyclo-hexyl group), 5.02 (s, 2H, CH2-CO), 6.51 (s, 1H, NH- cyclohexyl, D2O
exchangeable), 7.508.10 (m, 8H, Ar-H), 10.38 (s, 1H, CH2-CONH-Phenyl, D2O exchangeable), 10.99 (s, 1H, SO2NH, D2O
exchangeable); Anal. Calcd. For C25H29N5O5S (511.19): C, 58.69;
H, 5.71; N, 13.69; Found: C, 59.01; H, 5.84; N, 13.85%.

4.1.5.5. 2-(2-Ethyl-4-oxoquinazolin-3(4H)-yl)-N-{4-[N(phenylcar-bamoyl)sulfamoyl]phenyl}acetamide (25e). Brown crystal (yield 52%); m.p. 165167 LC; IR
(KBr, cm 1): 3309 (NH), 3046 (CH aro-matic), 2954 (CH aliphatic), 1714, 1646 (C@O), 1309, 1157 (SO2); 1H NMR (DMSO-d6) d ppm: 1.30 (t, 3H, CH3, J =
7.2 Hz), 2.812.89 (q, 2H, CH2-CH3, J = 7.2 Hz), 5.00 (s, 2H, CH2CO), 6.928.11 (m, 13H, Ar-H), 9.05 (s, 1H, NH-Phenyl, D2O exchangeable), 9.05 (s, 1H,
SO2NH), 10.94 (s, 1H, CH2CONH-Phenyl, D2O exchangeable), 11.07 (s, 1H, SO2NH, D2O exchangeable);13C NMR (DMSO-d6, 100 MHz) d (ppm): 10.9,
27.0, 48.2, 118.3(2), 119.8, 122.1(2), 123.3, 124.1, 127.1, 128.2, 128.8(2), 129.6(2), 133.9, 137.2, 139.1, 140.2,
143.5, 153.4, 155.2, 160.9, 166.4; DEPT (DMSO-d6, 100 MHz) d (ppm):10.9(1CH3), 27.0(1CH2), 48.2(1CH2), 118.2(2), 122.1(2), 123.3, 124.1, 127.1, 128.2,
128.8(2), 129.6(2), 133.9(13CH); Anal. Calcd. For C25H23N5O5S (505.14): C, 59.40; H, 4.95; N, 13.85; Found: C, 59.63; H, 4.62; N, 14.01%.

4.1.5.6. 2-(2-Ethyl-4-oxoquinazolin-3(4H)-yl)-N-{4-[N(butylcar-bamoyl)sulfamoyl]phenyl}acetamide (25f). Brown crystal (yield 45%); m.p. 152154 LC;
IR(KBr, cm 1): 3352 (NH), 2949 (CH alipha-tic), 1689 (C@O); 1H NMR (DMSO-d6) d ppm: 0.83 (t, 3H, CH2-CH2-CH2-CH3), 1.20 (t, 3H, quinazoline-CH2-
CH3), 1.331.55 (m, 2H, CH2-CH2-CH2-CH3), 2.862.97 (q, 2H, CH2-quinazoline), 3.053.11 (m, 2H, CH2-CH2-CH2-CH3), 3.593.74 (t, 2H, CH2-CH2CH2-
CH3), 5.05 (s, 2H, CH2CO), 5.94 (s, 1H, NH-butyl, D2O exchangeable),
7.308.22 (m, 8H, Ar-H), 10.52 (s, 1H, CH2CONH-Phenyl, D2O exchangeable), 11.09 (s, 1H, SO2NH, D2O exchangeable); 13C NMR (DMSO-d6, 100 MHz) d
(ppm): 10.9, 14.1, 19.6, 131.9, 139.8, 143.2, 148.5, 118.6(2), 120.0, 126.5, 126.9, 127.9, 129.1(2), 135.2,
139.3, 142.5, 146.8, 149.5, 159.6, 162.3, 166.7; DEPT (DMSO-d6, 100 MHz) d (ppm): 10.9(1CH3), 14.1(1CH2), 19.6(1CH2), 131.9 (1CH2), 139.8(1CH2),
143.2(1CH2), 148.5(1CH2), 118,6(2), 126.5, 129.9, 127.9, 129.1(2), 135.2(8CH); Anal. Calcd. For C 23H27N5O5S (485.17): C, 56.89; H, 5.61; N, 14.42; Found:
C, 57.04; H, 5.74; N, 14.70%.

4.1.5.7. 2-(6-Bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-{4-[N(cy-clohexyl carbamoyl)sulfamoyl]phenyl}acetamide (25g). Yellow crys-tal (yield 72%); m.p.

224226 LC; IR (KBr, cm 1): 3312, 3228 (2NH), 3071 (CH aromatic), 2930 (CH aliphatic), 1684 (C@O), 1336, 1163 (SO2); 1H NMR (DMSO-d6) d ppm: 1.16
1.65 (m, 10H, cyclohexyl group), 2.54 (s, 3H, CH3), 3.32 (m, 1H, of cyclohexyl group), 4.95 (s, 2H, CH2), 6.40 (s, 1H, NH-cyclohexyl, D2O exchangeable), 7.58
(d, J = 8.8 Hz, 1H, Ar-H),7.68 (d, J = 8.8 Hz, 2H, Ar-H), 7.75 (d, J = 8.8 Hz, 2H, Ar-H), 7.96 (d, J = 6.4 Hz, 1H, Ar-H), 8.03 (d, J = 6.4 Hz, 1H, Ar-H), 8.42 (s,
1H, Ar-H), 10.32 (s, 1H, CH2CONH-Phenyl, D2O exchangeable), 10.95 (s, 1H, SO2NH, D2O exchangeable); Mass: 575 (M+, 1.52%), 577 (M+2, 1.63%), 233
(27.93%), 146 (100% base beak), 119 (44.19%), 90 (37.61%); Anal. Calcd. For C 24H26BrN5O5S (575.08): C, 50.01; H, 4.55; N, 12.15; Found: C, 50.34; H,
4.59; N, 12.34%.

4.1.5.8. 2-(6-Bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-{4-[N (phenylcarbamo-yl)sulfamoyl]phenyl}acetamide (25h). Brown crys-tal (yield 54%); m.p.

235237 LC; IR (KBr, cm 1): 3313, 3129 (2NH), 3065 (CH aromatic), 1647 (CO); 1H NMR (DMSO-d6) d ppm: 2.55 (s, 3H, CH3), 5.02 (s, 2H, CH2), 6.917.45
(m, 12H, Ar-H), 9.12 (s, 1H, NH-Phenyl, D2O exchangeable), 10.42 (s, 1H, CH2-CONH-Phenyl, D2O exchangeable), 11.34 (s, 1H, SO2NH, D2O exchangeable);
Anal. Calcd. For C24H20BrN5O5S (569.04): C, 50.54; H, 3.53; N, 12.28; Found: C, 50.69; H, 3.58; N, 12.39%.
4742 M.K. Ibrahim et al. / Bioorganic & Medicinal Chemistry 25 (2017) 47234744

4.1.5.9. 2-(6-Bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-{4-[N (butylcarbamoyl)sulfamoyl]phenyl}acetamide (25i). Brown crystal (yield 49%); m.p. 212
214 LC; IR (KBr, cm 1): 3332 (NH), 3077 (CH aromatic), 2956 (CH aliphatic), 1682 (C@O), 1318, 1157 (SO2); 1H NMR (DMSO-d6) d ppm: 0.77 (t, 3H, CH2-
CH3), 1.22 1.27 (m, 2H, CH2-CH3), 1.421.47 (m, 2H, CH2-CH2-CH3), 2.58 (s, 3H, CH3-quinazoline), 2.912.93 (t, 2H, CH2-CH2-CH2-CH3), 5.01 (s, 2H,
CH2-CO), 7.26 (s, 1H, NH-butyl, D2O exchangeable), 7.57 8.23 (m, 6H, Ar-H), 8.42 (s, 1H, Ar-H), 10.52 (s, 1H, CH2CONH-Phe-nyl, D2O exchangeable),
10.96 (s, 1H, SO2NH, D2O exchangeable); 13C NMR (DMSO-d6, 100 MHz) d (ppm): 13.8, 19.7, 22.4, 31.9, 39.6, 48.3, 119.1(2), 121.5, 124.0, 127.3, 129.5(2),
130.5, 138.0, 139.1, 142.0, 147.5, 156.6, 159.9, 161.6, 166.5; DEPT (DMSO-d6, 100 MHz) d (ppm): 13.8(1CH3), 19.7(1CH2), 22.4(1CH3), 31.9 (1CH2),
39.6(1CH2), 48.3(1CH2), 119.1(2), 127.3, 129.5(2), 130.5, 138.0(7CH); Anal. Calcd. For C 22H24BrN5O5S (549.07): C, 48.01; H, 4.40; N, 12.72; Found: C,
48.23; H, 4.49; N, 12.97%.

4.2. Biological evaluation

4.2.1. In vivo anti-hyperglycemic activity

Anti-hyperglycemic activity evaluation of the title compounds was determined in vivo using STZ induced hyperglycemic rats according to biological method
described by Ramsey et al.39 as follows.

Swiss albino adult male rats, weighing 200300 g, were used as test animals, conducted with approval from the Ethics Committee (approval#23PD/3/12/8R)
of Al-Azhar University, Nasr City, Cairo, Egypt. All the experiments were carried out according to the respective international guidelines. At first, the rats were
housed under well-ventilated conditions at room temperature (2530 LC) without any stressful stimuli. They were allowed to acclimatize with free access to food
and water for 24 h period before testing except during the short time they were removed from the cages for testing. For induction of diabetes, streptozotocin
(STZ) (SigmaAldrich Chemical Co, Milwaukee, WI, USA.) dissolved in 0.90 % sodium citrate buffer (pH 4.50) was injected intraperi-toneally (i.p) in a dose of
60.00 mg/kg.61 After 3 days, the level of blood sugar was determined by glucometer (Taiwan). The rats with blood glucose levels higher than 250.00 mg/dl were
selected for anti-diabetic tests. The diabetic rats were randomly arranged in 18 groups, each of six animals. The synthesized compounds and reference drugs were
suspended in 1% gum acacia. Fifteen groups were administered the synthesized compounds orally in aldose of 20.00 mg/kg. One group served as diabetic control
which was fed with 1% gum acacia. The last two groups served as standard control, where one received glimepiride (0.36 mg/kg) orally, and the other received
rosiglitazone (2.7 mg/kg) orally. Blood samples were collected from the rat tail at 0 and 3 h after drug administra-tion, blood glucose levels were measured
immediately by glu-cometer. The median of % reduction in blood glucose levels was calculated.

4.2.2. In vitro of PPARc- ligand binding assay

The most active compounds with in vivo anti-hyperglycemic activity (19a, 19b, 19c, 19d, 19f, 25a, 25c, 25d, 25f and 25g) were used as representative
samples to determine the binding affinity of syn-thesized compounds toward PPARc. Fluorescence Polarization Assay technique40 using Polar Screen TM PPARc-
Competitor Assay Kit (Invitrogen, Carlsbad, CA) was carried out. The procedure was conducted according to the manufacturers instructions as follows.
The Test compounds and the positive control, rosiglitazone, were dissolved in DMSO with concentrations of 0.0170 lg/ml. The ligand binding domains of
PPARc (LBD) expressed as glu-tathione S-transferase (GST) and FluormoneTM PPARc green, a tight
binding, selective, fluorescent PPARc ligand, were mixed with test compounds and rosiglitazone.
The PPARc and FluormoneTM Tracer form a NR/FluormoneTM Tra-cer complex, resulting in a high polarization value. Compounds that displace the
FluormoneTM Tracer from the NR/FluormoneTM Tra-cer complex cause a decrease in polarization. Displaced Fluor-moneTM Tracer tumbles rapidly, resulting in a
low polarization. The polarization remains high in the presence of compounds which do not displace the Fluormone TM Tracer from the complex. The shift in
polarization value in the presence of test compounds is used to determine relative affinity of test compounds for the NR. Displace-ment of the fluorescent ligand
was assessed by measuring loss of fluorescence polarization using a SpectraMax M5 plate reader. From dose repose curve, IC 50 (Concentration of compound
required to displace 50% of titrated ligand) was calculated.

4.2.3. In vitro insulin assay

The most active compounds as vivo anti-hyperglycemic agents (19a, 19b, 19c, 19d, 19f, 25a, 25c, 25d, 25f and 25g) were dissolved in DMSO at a
concentration of 5, 10, 15, 20 lM. Wistar rats (250300 g) were injected intraperitoneally with a 0.2% pilo-carpine solution (0.2 ml). Pancreatic islets of these rats
were iso-lated by the collagenase method to obtain 300400 islets from each pancreas.62 The isolated islets were cultured for 12 h in glu-cose 16 mmol/l in
CMRL-1066 medium containing, 10 mg/ml gen-tamycin, 2 mmol/l l-glutamine and 10% FCS at 37LC in a 95% air/5% CO2 atmosphere for 1 h in the presence
and the absence of tested compounds solutions. Using Ringer HEPES buffer, the cul-tured islets were washed two successive times. Then, they were incubated
for 30 min at 37 LC with glucose 16.7 mmol/l. The Insu-lin level was quantitatively estimated using Rat Insulin ELISA Kit (Thermo Fisher Scientific Inc., USA),
according to manufacturers instructions.

This test employs the quantitative sandwich enzyme immunoassay technique. 41 Antibody specific for rat insulin (biotinylated anti-rat insulin antibody) has
been pre-coated onto a microplate. Standards (recombinant rat insulin, 100 ll) and sam-ples (100 ll) were pipetted into the wells followed by incubation for 2.5 h
at 25 LC with gentle shaking. Then, solutions were dis-carded and the wells were washed 4 times with 1 Wash Solution. After the last wash, the remaining wash
buffer was removed by decanting. Next, 100 ll of 1 prepared biotinylated antibody was added to each well and incubated for 1 h at room temperature with gentle
shaking. Then, washing was performed as before. The pre-pared Streptavidin-HRP solution (100 ll) was added to each well followed by incubation for 45 min. at
room temperature with gen-tle shaking. The solution was discarded and washed. TMB One-Step Substrate Reagent (100 ll) was added to each well followed by
incubation for 30 min. at room temperature in the dark with gentle shaking. Stop Solution (50 ll) was added to each well and the absorbance was read
immediately at 450 nm. From a dose response curve, EC50 of the compounds were determined.

4.3. Molecular modeling

Molecular docking with the prepared enzyme and Pharma-cophore model were generated using the Discovery Studio 2.5.

4.3.1. Docking
Molecular docking studies were performed to provide insights of molecular binding modes of the tested compounds inside the pocket of PPARc. All the
synthesized compounds were docked against PPAR c using DiscoveryStudio 2.5 to evaluate the free ener-gies and binding mode of the proposed molecules with
the active site of PPARc. The selection of the most promising molecules depends on the correct binding mode and the binding free energy
 M.K. Ibrahim et al. / Bioorganic & Medicinal Chemistry 25 (2017) 47234744 4743

(DG). The 3D crystal structure of PPARc (PDB ID- 4EMA) was downloaded from PDB, resolution of 2.55 , water molecules were removed from downloaded
protein. Crystallographic disorders and unfilled valence atoms were corrected using alternate conforma-tions and valence monitor options. Protein was subjected
to energy minimization by applying CHARMM force fields for charge, and MMFF94 force field for partial charge. Inflexibility of structure was obtained by
creating fixed atom constraint. The binding site of the protein (4EMA) was defined and prepared for docking. The 2D structures of rosiglitazone and the designed
compounds were sketched using ChemBioDraw Ultra 14.0 and saved in MDL-SDfile format. The saved file was opened, 3D structures were protonated and
energy was minimized by applying CHARMM force fields for charge, and MMFF94 force field for partial charge. Then, they were prepared for docking by
optimization of the different the parame-ters. Molecular docking was performed using CDOCKER protocol which is an implementation of the CDOCKER
algorithm. CDOCKER is a grid-based molecular docking method that employs CHARMM-based molecular dynamics (MD) scheme to dock ligands into a
receptor binding site. The receptor was held rigid while the ligands were allowed to be flexible during the refinement. After that the docking scores (-CDOCKER
interaction energy) of the best-fitted conformation of each of the docked molecules with the amino acids at the PPAR c binding pocket were recorded (Table 2).

4.3.2. Pharmacophore studies

A set of thirty compounds containing a sulfonylurea scaffold were selected from the literature 46,47 (Fig. 14). The data sets were
divided into two groups; training set (nineteen compounds) and test set (twelve compounds) of diverse structures and variable activities. The training set was used
for generation of pharma-cophore model, where the test set was utilized to validate the gen-erated pharmacophore hypotheses. Glimepiride, one of test set group,
was considered as the reference SU agonist. The generation of the pharmacophore model for SUR modulators was accom-plished using Discovery Studio 2.5
software. Molecules were built and conformational models for each compound were generated automatically using the prepare ligand protocol. The prepared
training set molecules were used for generation 3D pharma-cophore using Catalyst HypoGen algorithm generation protocol. In this study, the chosen features to
be considered in pharma-cophore generation were hydrogen bond donor (HBD), hydrogen bond acceptor (HBA), negative ionizable, hydrophobic aliphatic (HA)
and ring aromatic (RA). Based on these criteria, virtual screen-ing was carried out via the ligand pharmacophore mapping proto-col. The best predictive model
was used as 3D queries to identify potential leads against SUR from the newly synthesized compounds

4.3.3. QSAR studies

The structures of training set compounds (19ad, 19f, 25a, 25c,d, 25f,g, 28a,b, 28d,e, 29a,b and 30a,b) were first sketched using Chem-BioDraw Ultra 14.0
and saved in MDL-SD file format. Next, the SD file was opened by Discovery studio 2.5 software. Then, the ligands were prepared by application of force fields
via CHARMM and MMFF94. After preparation of ligands, molecular descriptors were predicted from general purpose (calculate molecular proper-ties). Selected
descriptors of the tested derivatives were used to build a QSAR model by one of the best method, Multiple Linear Regression (MLR) analysis.48

4.3.4. In silico ADMET analysis

Absorption, distribution, metabolism, excretion and toxicity (ADMET) prediction was carried out with the ADMET descriptor module of the small molecules
protocol of Discovery studio 2.5 software.
Conflict of interest

None.

Acknowledgements

Authors are thankful to prof. A. Mansour, pharmacology depart-ment, faculty of pharmacy, Al-Azhar University, Cairo, Egypt, as well as the biologists of
VACSERA CO., Giza, Egypt for providing laboratory facilities for biological studies.

A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmc.2017.07.015. These data include MOL
files and InChiKeys of the most important compounds described in this article.
La mayor parte de las terapias usadas corrientes para el tratamiento de la diabetes del tipo 2 se descubrieron y se
desarrollaron en ausencia de objetivos moleculares biolgicos definidos. Adems, tienen varios efectos adversos que
comprometen a los pacientes vidas.
El conocimiento emergente de los mecanismos patgenos claves ha llevado a la identificacin de varios objetivos de
la medicina moleculares.
La consideracin de estos hechos, la exploracin de nuevas medicinas antidiabticas potentes son muy cruciales.
Dos (receptores) objetivo de la medicina moleculares principales se implican en el tratamiento de la diabetes del tipo
2 mellitus; receptores de sulfonylurea (SUR) y peroxisome receptores proliferator-activados (PPARs). Receptores de
Sulfonylurea presentes en pancretico b las clulas pueden ser estimuladas por sulfonylureas para aumentar la
secrecin de la insulina. Se relat que segunda y tercera generacin sulfonylureas como el glipizide y glimepiride,
respectivamente, relacinese con el A y sitios B en el SUR (Fig. 1A). Adems, ejercen la eficacia clnica actuando a
travs de no slo SUR sino tambin PPAR. c
. El modelo de Pharma-cophore para sulfonylurea medicinas interpretadoras se dise a

Fig. 1. A) Modelo Pharmacophoric para sulfonylurea agonists y algn sulfonylureas selectivo para tratamiento de
diabetes del tipo
2. B) Los rasgos estructurales esenciales de PPAR agonists y algunos compuestos relatados.
C) anti-hyperglycemic relatado quinazolin-4 (3H) - derivados.
contenga tres centros de lipophilic separados por amidic y anionic linkers (Fig. 1A).
Peroxisome los receptores proliferator-activados (PPARs) son ligando activ factores de transcripcin que pertenecen
a la superfamilia del receptor hormonal nuclear. Tres PPAR isotypes se han identificado, PPAR a, d, y c que se
implican en la regulacin de glucosa y lpido homeostasis. PPAR es mem-bien caracterizado ber de la subfamilia
PPAR.El papel central en metabolismo de glucosa y almacenaje de cido graso ha hecho PPAR
el objetivo farmacolgico ms deseable para el desarrollo de insulina que sensibiliza anti-hyperglycemic agentes.
Los rasgos estructurales bsicos de PPAR los agonist son una cabeza cida, un linker atado a un andamio aromtico
(grupo del espaciador), otro linker y una cola lipophilic hetero-aromtica (Fig. 1B).
7
Thi-azolidinediones (TZDs) como rosiglitazone , pioglitazone , dar-glitazone y troglitazone mostr afinidades altas
hacia PPAR.
(Fig. 1B). Thiazolidinediones son los agentes nicos clnicamente disponibles que controlan la hiperglucemia
mejorando la resistencia de la insulina. Lamentablemente, TZDs expuso efectos adversos serios relacionados con el
sistema cardiovascular. Se ha descubierto que un gran nmero de ligands sinttico non-TZDs modula PPAR actividad
como compuestos.Varios informes sugirieron que non-TZDs tengan ms potencial para reducir la glucosa y mejorar
dyslipidemia que rosiglitazone o pioglitazone. De modo que, puedan ser superiores del tratamiento de la diabetes del
tipo 2 mellitus con dyslipidemia anormal comparado con rosiglitazone y pioglitazone. Adems, el non-TZD PPAR el
agonists expuso efectos beneficiosos similares a ese de TZDs en modelos de animal, pero sin los efectos adversos
asociados.Algunos quinazolin-4 sintticos (3H) - derivados se relataron tener actividades anti-hyperglycemic como
ejemplificado por compuestos 11 y 12

(Fig. 1C)
En aos recientes, la filosofa del diseo de la medicina ha sido la transaccin - formado de una medicina un
objetivo a una medicina objetivos mltiples, acuado como polifarmacologa. Los fenmenos polifarmacolgicos
incluyen la medicina sola que afecta a objetivos mltiples de un camino de la enfermedad nico.
Las medicinas diseadas para actuar contra objetivos moleculares individuales no pueden combatir por lo general
enfermedades multigenic como el cncer o enfermedades que afectan tejidos mltiples o tipos de la clula como
diabetes y desrdenes inmunes e inflamatorios. Las medicinas que afectan objetivos mltiples simultneamente son
mejores en el control de sistemas de la enfermedad complejos, son menos propensas a la resistencia a los
medicamentos y son el estndar de cuidado en muchas reas teraputicas importantes.
En esta revisin, nosotros aqu en informe la sntesis de nuevo non-TZDs quinazolin-4 (3H) - un ligands que lleva
sulfonylurea mitades, apuntando a obtenido unas actividades agonistic duales contra PPAR y SUR

1.1. Razn fundamental de diseo molecular. Hay semejanzas estructurales considerables entre los rasgos de SUR y
PPAR agonists, en consecuencia, diseamos y sintetizamos nuevos compuestos contienen ambos rasgos (Fig. 2). La
mitad sulfonylurea sirvi de una cabeza cida requerida para PPAR actividad de agonistic a travs de formacin de
enlaces de hidrgeno fundamentales con serine289, tyrosine473, histidine323 e histidine449 del PPAR . Las substituciones
aromticas y aliphatic en mitades sulfonylurea sirvieron como lipophilic centros requeridos para SUR agonists.
Adems, el grupo de NH de mitad de la sulfonamida es cidos orgnicos dbiles (pKa = 5.2 6.2) y en gran parte se
ioniza en el pH fisiolgico f orming un anionic linker que contribuye considerablemente a SUR agonistic la afinidad.
Por otra parte, POR TANTO
2
el grupo sirvi de un espaciador del tomo entre el jefe cido y el grupo aromtico, dando la longitud ptima para
PPAR actividad de agonistic. el para-disubstituted phenyl grupo jug como un grupo del espaciador y un centro de
lipophilic requerido para PPAR y SUR agonists, respectivamente. Un acetamido (CH2- CONH ) el grupo se us
como un linker entre la cola lipophilic y el grupo del espaciador. El amido (CONH) el grupo dio a nuestros
compuestos la oportunidad de relacionarse con sitios A y B de SUR. Adems, estos linkers se sintetizaron con
longitudes diferentes y posiciones del accesorio diferentes en quinazolin-4 (3H) - un ncleo a fin de estudiar SAR de
nuestros compuestos.Finalmente, quinazolin-4 (3H) - un ncleo sirvi de una cola cclica y un centro de lipophilic
requerido para PPAR y SUR agonistic actividades, respectivamente. Tres consideraciones diferentes nos llevaron a
elegir quinazolin-4 (3H) - un ncleo; en primer lugar, la actividad anti-hyper-glycemic relatada de algn quinazolin-4
(3H) derivados. En segundo lugar, bicyclic la estructura de quinazolin-4 (3H) - un ncleo es conveniente para el
brazo hydrophobic puesto la talla grande II de PPAR. En tercer lugar, los tomos del nitrgeno de quinazolin-4 (3H) -
uno puede aumentar la actividad agonistic sirviendo de aceptadores de la obligacin de hidrgeno.

2. Resultados y discusin

2.1. Qumica

Los compuestos iniciales, 3--2-sul-fanylquinazoline-4 (4-substitutedphenyl) (3H) - one, 15,estuvieron preparados por
una reaccin del pote de cido anthranilic con 4-methylaniline 14 y 4-methoxylaniline en metanol que funde de
nuevo en la presencia de carbn disulfide e hidrxido del potasio. Reaccin de compuestos con hidrxido del potasio
alcohlico permitido los derivados de sal del potasio correspondientes. La calefaccin del potasio producido sala con
el 2-chloro-n-acetamide (4-sulfamoylphenyl) en DMF seco con la cantidad cataltica de KI se permiti los
intermedios claves,en relativamente altas prestaciones (el 81% y el 79%, respectivamente). Ms sobre el tratamiento
de compuestos,con los derivados isocyanate apropiados a saber, cyclohexyl el isocyanate, butyl Iso-cyanate y phenyl
isocyanate en la acetona seca en la presencia del carbonato del potasio anhidro como la base, produjo el objetivo
sulfonylurea derivados, respectivamente
(el Esquema 1). La reaccin de cido anthranilic con anhdrido actico y anhdrido propionic, permitido los derivados
benzoxazine correspondientes , respectivamente
.
El cido 4-bromoanthranilic con el anhdrido actico dio el derivado benzoxazine correspondiente
Reaccin subsecuente de con formamide produjo 2 alkyl 6 substitutedquinazoline 4 (3H) - derivados
, respectivamente. La reaccin de compuestos con hidrxido del potasio alcohlico permitido los derivados de sal del
potasio correspondientes, respectivamente. La calefaccin del potasio obtenido sala con el 2-chloro-n-acetamide (4-
sulfamoylphenyl) en DMF seco con la cantidad cataltica de KI se permiti los intermedios claves en producciones
relativamente buenas (el 76% y el 74%, respectivamente). Reaccin de compuestos con isocyanates apropiado a
saber, el cyclohexyl isocyanate, butyl isocyanate y phenyl isocyanate en la acetona seca en la presencia de carbonatos
del potasio anhidros se permiti sulfonylureas correspondiente, respectivamente
(el Esquema 2). En cuanto a los compuestos claves , los espectros IR revelaron la presencia de dos NH caractersticos
y NH grupos de absorcin de mitad 4-aminobenzenesulfonamide aproximadamente 3229 3352 cm , adems de grupos
de absorcin debido a CO grupos de quinoxaline y mitades amide alrededor de 16801673 cm . El H NMR espectros
revel la presencia de DO pico de la camiseta cambiable de NH de la mitad de la sulfonamida en aproximadamente 7.2 ppm y
una camiseta alcanzan su punto mximo para el grupo del metileno de grupo acetamido en aproximadamente 4.1 ppm.

Los espectros del DEPARTAMENTO de compuesto diferenciado el C hace seas para ser; un CH en 21.4 ppm y un
CH en 37.4.
Para los compuestos objetivo, los espectros IR mostraron la desaparicin de la sulfonamida NH el pico y el aspecto
de ms camiseta deshielded alcanzan su punto mximo para NH de la mitad sulfonylurea. Al mismo tiempo,
mostraron grupos de absorcin agudos de 3NH los grupos de la mitad 4-aminobenzenesulfonylurea en la regin

Fig. 2.
Los compuestos sintetizados con rasgos pharmacophoric estructurales bsicos de SUR y PPAR 33573309 cm. El H
NMR espectros mostr la desaparicin de la sulfonamida NH pico y aspecto de ms deshielded dos picos de la
camiseta para 2NH de sulfonylurea. Los espectros del DEPARTAMENTO de compuesto mostr 5 CH adicionales
caracterstica de seales para cyclohexyl mitad.

2.2. Pruebas biolgicas

2.2.1. En vivo anti-hyperglycemic actividad.

El en vivo anti-hyperglycemic actividad de compuestos, se evalu contra hyperglycemic streptozotocin-inducido
ratas usando anti-hyperglycemic ensayo. Rosiglitazone y glimepir-ide como dos de las medicinas antidiabticas ms
activas, se usaron como el control. Los resultados se relataron como la reduccin de % del nivel de glucosa de la
sangre (la Tabla 1). Los compuestos probados expusieron actividades anti-hyperglycemic buenas, moderadas o
dbiles. Compuesto se encontr ser el miembro ms potente (reduccin de % del nivel de glucosa de la sangre de
46.42). Adems, compuestos 25g, actividades anti-hyperglycemic fuertes mostradas (reduccin de % de 40.43, 41.23
y 42.50, respectivamente). Algunos compuestos mostraron actividades anti-hyperglycemic moderadas
como (reduccin de % de 33.42, 37.76, 38.64, 34.25 y 38.44, respectivamente). Adems, compuestos eran
dbilmente activos con valores de reduccin de % en los lmites de 19.66 a 29.22.

Tabla 1 En reduccin vivo de niveles de glucosa de la sangre, de vitro PPAR afinidades obligatorias y en actividades
de secretacin de la insulina vitro de compuestos sintetizados y medicinas de la referencia.

2.2.2. En vitro PPAR- ligand que liga ensayo

Los compuestos ms activos ( ) se evaluaron adelante para tasar su en vitro PPAR afinidades obligatorias, usando
tcnica del Ensayo de Polarizacin de la Fluorescencia. Rosiglitazone se us como un control. Compuestos expuesto
las afinidades ms altas contra PPAR con IC valores de 0.371, 0.350, 0.369, 0.408 y 0.353mM, respectivamente. Se
not que el PPAR las afinidades obligatorias de los compuestos probados son menos que ese de rosiglitazone (IC
50 = 0.298 mM). Por otra parte, compuestos mostr PPAR moderado afinidades obligatorias con IC valores en los
lmites de 0.402 a 0.590 mM. Adems, compuesto expuesto una afinidad dbil con IC valor de 0.980 mM (de la
Tabla 1).
2.2.3. En ensayo de la insulina vitro

En actividades vitro que secretan la insulina de los compuestos ms activos ( ) se evaluaron contra islotes
pancreticos aislados de ratas va la enzima del bocadillo cuantitativa immunoassay tcnica. Glimepiride se us como
un control. Los resultados se relataron como la CE valores (la Tabla 1). Los compuestos probados mostraron bien,
moderado a actividades insu-lin-secreting dbiles. Compuestos expuesto las actividades ms altas que secretan la
insulina con la CE valores de 0.97, 1.01 y 1.15 mM, respectivamente. El control, glimiperide mostr la CE de 0.79
mM. Adems, compuestos han demostrado actividades moderadas que secretan la insulina con La CE valores de
1.31, 1.53 y 1.68 mM, respectivamente, mientras compuestos actividades dbiles expuestas con la CE valores de
3.09, 2.69, 2.91 y 2.51 mM, respectivamente.
2.3. Modelado molecular

El atraque, pharmacophore generacin, QSAR y estudios de ADMET se realiz usando el software Discovery Studio
2.5 (Accelrys Inc., San Diego, California, los EE. UU). La estructura diseo de la medicina basado (atraque) tcnica
usada como un gua para investigar el modo obligatorio del objetivo compone con PPAR. Por otra parte, la estructura
de cristal para SUR no est disponible, como consiguiente, ligand diseo de la medicina basado (pharmacophore)
tcnica se us como un gua para predecir el sulfonylurea agonistic las actividades de los compuestos sintetizados. El
tanto atraque como modelado de pharmacophore dio una idea sobre la interaccin que existira entre el ligand y el
receptor.
2.3.1. Atraque de estudios

Los estudios de atraque moleculares de los compuestos titulados se realizaron a fin de racionalizar los resultados
biolgicos obtenidos as como ayudar en el entendimiento de varias interacciones entre el ligands y el sitio activo de
PPAR en detalles.
El PPAR la cavidad es Y-shaped y consiste en una entrada, brazo I y brazo II. El brazo I contiene cuatro residuos
polares, Tyr473, His323, Ser289 e His449. Estos residuos implicados en red de la obligacin de hidrgeno entre el
receptor y ligands. El brazo II se forma de Ile281, Ile341, Val339 y Leu353, mientras la entrada consiste en Arg288,
Leu330, Ser342 y Leu333. La mitad thiazolidinedione polar cida se dirigi en el brazo polar I del receptor. Al
mismo tiempo, el grupo imide form un enlace de hidrgeno con una distancia de 2.35 con Tyr473 (AH) a travs
de su hidrgeno cido. Adems, la cola hydrophobic ocup el bolsillo hydrophobic (brazo II y la parte hydrophobic
de la entrada). Se encontr que estos resultados eran consecuentes con los datos relatados
45
(Fig. 3). El modo obligatorio propuesto de la referencia ligand, rosiglita-zona, expuso un valor de afinidad de-47.44
kcal/mol. Mostr interacciones diferentes importantes con los residuos esenciales en el sitio activo de PPAR

(Fig. 4). Los resultados del estudio que atraca en la Tabla 2 indicaron que todos estudiaron ligands expuso una
posicin similar y orientacin dentro del sitio de unin esencial de PPAR . Todas las molculas diseadas mostraron
energas de enlace buenas en los lmites de 35.01 a 58.60 kcal/mol. Compuesto mostr un valor de afinidad de
51.42 kcal/mol con 4 H-obligaciones (Fig. 5).
La cabeza polar cida (sulfonylurea mitad) se orient en el brazo polar I. Form dos enlaces de hidrgeno con los
residuos polares Ser289 y Cys285 en el brazo I. El hidrgeno cido del grupo sulfamoyl form un enlace de
hidrgeno de 2.00 con Ser289 (AH), y el oxgeno del grupo carbamoyl form un enlace de hidrgeno de 2.30
con Cys285. Quinazolin-4 (3H) - un ncleo se orient en la entrada hydrophobic. El hidrgeno de amide linker form
un enlace de hidrgeno de 2.3 con Leu340. El cuarto enlace de hidrgeno es 2.2 y se form entre el tomo de
azufre de linker y Ser342. Estas obligaciones explican la energa de enlace alta del compuesto con PPAR , y la
actividad biolgica de este compuesto.

El modo obligatorio propuesto de compuesto (el valor de afinidad de 55.38 kcal/mol y 2 H-obligaciones) era prcticamente
lo mismo como ese de rosiglitazone, donde su cabeza polar cida (sulfonylurea mitad)

Fig. 3.
PPAR cavidad formada de 3 brazo de partes principal I, brazo II y entrada 45

Fig. 4.
El modo obligatorio de rosiglitazone atrac en el sitio activo de PPAR la formacin de enlace de hidrgeno (punto
verde) entre su cabeza polar y tyr473.

Tabla 2

El atraque energas libres obligatorias de los compuestos sintetizados.

Leu340. El cuarto enlace de hidrgeno es 2.2 y se form entre el tomo de azufre de linker y Ser342. Estas
obligaciones explican la energa de enlace alta del compuesto con PPAR , y la actividad biolgica de este compuesto.

El modo obligatorio propuesto de compuesto (el valor de afinidad de 55.38 kcal/mol y 2 H-obligaciones) era prcticamente
lo mismo como ese de rosiglitazone, donde su cabeza polar cida (sulfonylurea mitad) ocup el brazo polar I. Form
dos enlaces de hidrgeno con los residuos polares Tyr473 y Ser289 en el brazo I. El tomo de oxgeno del TAN el
grupo form un enlace de hidrgeno de 2.29 con Tyr473 (AH). El tomo de hidrgeno del grupo carbamoyl form un enlace de
hidrgeno de 1.97 con Ser289 (AH) (Fig. 6). Estas obligaciones y modo obligatorio correcto explican la energa alta de
la encuadernacin del compuesto

2.3.2. Estudios de Pharmacophore

2.3.2.1. Generacin de modelo 3D-pharmacophore. El objetivo del principio de este procedimiento era producir el 3D
pharmacophore modelos en la luz de SU conocido agonists, que puede reflejar con eficacia el SAR de SU corriente
agonists. Un juego de treinta compuestos contiene -los ing un andamio sulfonylurea se seleccionaron de la literatura
para generar y validar el 3D pharmacophore modelo (Fig. 16). El modelo producido se utiliz como la pregunta de la
mirada 3D para tasar el SUR agonistic actividades para los compuestos sintetizados. Como mostrado en la Tabla
3, diez hiptesis se generaron. Todos ellos han costado diferencias que el coeficiente de correlacin y ms de 60
trozos valora ms alto que 0.90. Si la diferencia del coste es ms alta que 60 trozos, hay una gran posibilidad (ms del
90%) que el modelo representa una correlacin verdadera. Hypo-1 se seleccion para anlisis adicionales debido a su
coste total es el ms cercano al coste fijo, su RMS es el ms pequeo y el coeficiente de correlacin es el nivel ms
alto - est. El coste nulo, el coste fijo y los valores del coste total de hypo-1 son 127.30, 46.26 y 50.43 trozos ,
respectivamente. Hypo-1 cuestan la diferencia es 76.87, RMS es 0.72 y el coeficiente de correlacin es 0.98,
demostrando una capacidad de la prediccin buena. La gran mayora de hiptesis implic los rasgos siguientes;
aceptadores de la obligacin de hidrgeno (HBA), donante de la obligacin de hidrgeno (HBD), hydrophobic
aliphatic (HA) y anillo aromtico (RA) (la Tabla 3). Hypo-1 comprendi hydrophobic aliphatic (HA), aceptadores de
la obligacin de hidrgeno (HBA) del donante de la obligacin de hidrgeno (HBD) y anillo aromtico (RA) (Fig. 7).
El arreglo espacial y las distancias entre los rasgos pharmacophore de hypo uno se demuestra en Fig. 8. stos
estudian confirm la fiabilidad del modelo phar-macophore generado. La previsibilidad de Hypo-1 se tas usando
compuestos del juego de formacin dividido sobre la base de su escala de actividad en a; muy activo (+++, 1/C <10
mM), moderadamente activo (++, 10 mM 1/C <100 mM) e inactivo (+, 1/C 100 mM). Los resultados de validacin
indicaron que hay consecuencia marcado entre valores de actividad experimentales y preditos para toda la Tabla 4.
2.3.2.2 de compuestos de prueba . Validacin de Hypo-1 pharmacophore modelo. Esta progresin se hizo para
examinar la capacidad del modelo creado de distinguir estructuras activas y esperar sus actividades exactamente. Dos
mtodos se aplicaron para validar el hypo-1; prediccin de actividad del equipo de prueba y correlacin de
glimepiride como una referencia externa de pharmacophore generado

2.3.2.2.1. Prediccin de actividad del equipo de prueba. El mismo protocolo del juego de formacin se realiz para el
equipo de prueba de once compuestos (Fig. 14) para verificar la capacidad del modelo (hypo-1) pharmacophore
seleccionado de predecir las actividades de los nuevos compuestos sintetizados. Los resultados relatados demostraron
que hypo-1 es capaz de predecir y distinguir entre las actividades diferentes de compuestos activos e inactivos
eficazmente. Los valores de actividad experimentales y estimados de los compuestos del equipo de prueba se
pusieron en una lista en la Tabla 5. Correlacin de glimepiride. Glimepiride como una referencia externa se traz un
mapa con pharmacophore generado (hypo-1) y demostr un valor Adecuado alto de 8.58. la mitad cyclohexyl
completamente correspondi con AH, el grupo carbonyl de mitad de la urea equipada con HBA, el anillo de phenyl
central equipado con la Real Academia de Bellas Artes y el NH de amide linker equipado con el HBD (Fig. 9).

2.3.2.3. Valoracin de molculas diseadas. El 3D vlido pharma-cophore (Hypo-1) era usado para tasar las
actividades de molculas diseadas. Las molculas diseadas de la actividad se estimaron segn el nivel de prueba
con Hypo-1. Las actividades estimadas y los valores adecuados de los compuestos diseados se relataron en la Tabla
6. Se observ que la mayor parte de los compuestos diseados tienen valores alto Adecuados hacia Hypo1, indicando
prometiendo SUR agonistic actividades. Los compuestos empotrados se arreglaron segn su Se adaptars a valores en
el pedido inclinado como; 19d, 19a, 25g, 25a, 19f ,19c, 25d y 25f .
Correlacin de cuatro compuestos diseados (19a, 19c, 19f y 25g) en pharmacophore generado (el Hypo1) se
demostr en Higos. 10, respectivamente. Se not que el modelo de correlacin de stos compone es como lo mismo
como ese de glimepiride. Donde, los grupos alkyl (cyclohexyl y butyl) completamente equipado con AH, los grupos
carbonyl de mitades de la urea correspondieron con HBA, los anillos de phenyl centrales equipados con la Real
Academia de Bellas Artes y los grupos NH de amide linkers equipado con HBD. 2.3.3. Estudios de QSAR A fin de
identificar el efecto substituents en el PPAR afinidad obligatoria y capacidad que secreta la insulina, estructura
cuantitativa activ-la relacin de ity (QSAR) los estudios se realizaron usando el anlisis de la regresin lineal
mltiple (MLR) En el presente estudio, un juego de formacin de 18 derivados sulfonylurea se sujet al anlisis MLR
para la generacin modela. Este juego de formacin incluye el en el examen vitro - ined nuevos compuestos (
19a d, 19f , 25a, 25c,d y 25 f ,g ) as como ocho compuestos relatados. Los datos de actividad biolgica se
transformaron de IC y la CE valores en FOTO y pEC valores (es decir tronco IC y tronco la CE respectivamente y
usado como variables dependientes en los estudios de QSAR. Los descriptores moleculares usados (variables
independientes) son: i) propiedades moleculares como coeficiente de particin (AlogP), muela refrac-tivity (MR),
pKa, solubilidad molecular (MS), rea de superficie polar molecular (MPSA) y volumen molecular (MV), ii)
descriptores topolgicos como ndices de Balaban (JX y JY), la conectividad molecular de Kier (CHI0, CHI1, CHI2),
y descriptor de InfoContent terico por el Grfico (IC), iii) descriptores electrnicos 3D como momento del dipolo
(m), descriptores de Jurs (forma y descriptores electrnicos) como cargado por la superficie reas de superficie
parciales cobradas (WPSA1, WPSA2, WPSA3, WNS1, WNSA2 y WNSA3), rea de superficie positiva parcial
(PPSA1), rea de superficie negativa parcial (PNSA1), el precio total carg la rea de superficie positiva (PPSA2), el
precio total carg la rea de superficie negativa (PNSA2) y el precio atmico carg la rea de superficie positiva
(PPSA3) y iv) los ndices de la oposicin como shadow_Xlength (shadX), shadow_Y-longitud (sombreada) y
shadow_Zlength (sbalos).

Fig. 5. Modo obligatorio de compuesto atracado en el sitio activo de PPAR , formacin de enlaces de hidrgeno (verdes)
con los residuos polares (Ser289 & Cys285) en brazo I. mientras linker enlaces de hidrgeno formados con (Leu340
& Ser342) residuo de entrada.
Fig. 6. Modo obligatorio de compuesto atracado en el sitio activo PPAR, formacin de enlaces de hidrgeno (verdes) con
los residuos polares influyentes Tyr473 y Ser289 en brazo I.
Fig. 7. La mejor geometra 3D-pharmacophore hipottica (Hypo 1), con cuatro rasgos; verde (aceptador de la H-
obligacin), azul (hydrophobic aliphatic), morado (donante de la H-obligacin) y el marrn (suenan aromtico).
Fig. 8. Relacin espacial 3D y parmetros geomtricos de Hypo1. La distancia entre rasgos de pharmacophore se
relata en angstromes.
Fig. 9.
La correlacin de glimepiride en el nivel ms alto generado clasific pharmacophore (Hypo1).
Fig. 10. Correlacin de compuesto (valor adecuado = 8.09) en el nivel ms alto generado clasific pharmacophore
(Hypo1).
Fig. 11. Correlacin de compuesto(valor adecuado = 8.33) en el nivel ms alto generado clasific pharmacophore
(Hypo1).
Fig. 12. Correlacin de compuesto(valor adecuado = 8.24) en el nivel ms alto generado clasific pharmacophore
(Hypo1).

Fig. 13.
Correlacin de compuesto 25 g (valor adecuado = 7.48) en el nivel ms alto generado clasific pharmacophore
(Hypo1).

Fig. 14.Predito contra FOTO experimental del juego de formacin compone againstPPAR segn Eq.(r2= 0.809)
Fig. 15. Preditocontra pEC experimental del juego de formacin compone contra SUR segn Eq. (3 (r2= 0.915).

rea de superficie negativa (PNSA1), el precio total carg la rea de superficie positiva (PPSA2), el precio total carg
la rea de superficie negativa (PNSA2) y el precio atmico carg la rea de superficie positiva (PPSA3) y iv) los
ndices de la oposicin como shadow_Xlength (shadX), shadow_Y-longitud (sombreada) y shadow_Zlength
(sbalos).

El anlisis preliminar mostr algunos descriptores moleculares seleccionados para los compuestos probados (la Tabla
7). Segn un anlisis de correlacin, dos matrices de correlacin se construyeron para los compuestos del juego de
formacin hacia PPAR afinidad obligatoria (la Tabla 8) y capacidad que secreta la insulina de (la Tabla 9). En cuanto
a la afinidad obligatoria contra PPAR , se observ colinearity alto (r> 0.5) entre parmetros diferentes. Una
interrelacin alta (SR., r = 0.99) se observ entre parmetros topolgicos (CHI0, CHI1, CHI2) y muela refractivity.
Mientras la interrelacin baja (r <0.600) se observ entre pKa y parmetro topolgico, HBA, MV y MPSA. Las
correlaciones de descriptores moleculares diferentes con PPAR la afinidad obligatoria se presenta en la Tabla 10. La
matriz de correlacin (la Tabla 8) indic el predominio del parmetro lipophilic como el coeficiente de particin
(Alog P), muela refrac-tivity (MR), rea de superficie polar molecular (MPSA) y descriptores de Jurs (PPSA1 y
WPSA1) en la descripcin del PPAR afinidad obligatoria de Aqu y a partir de entonces, n: nmero de funciones de
datos; r: coeficiente de correlacin; r2: valor del coeficiente de correlacin cuadriculado, r2(adj): r2 ajustado para el
nmero de trminos en el modelo; r2 (pred): valor del coeficiente de correlacin cuadriculado proftico, equivalente
aq 2 de un leave-1-out cruzan la validacin y s: error lo menos cuadrado.

A fin de mejorar el valor del coeficiente de correlacin, conectamos ALog P con muela refractivity (MR), rea de
superficie polar molecular (MPSA), la rea de superficie positiva parcial (PPSA1) y cargado por la superficie cobr
reas de superficie parciales (WPSA1), que caus el mejor modelo QSAR para PPAR afinidad obligatoria de los
compuestos del juego de formacin (Eq. (2)). Este modelo QSAR se represent grficamente dispersando complots
del experimental contra PPAR predito la afinidad obligatoria valora la FOTO ya que el juego de formacin compone
como mostrado en Fig. 14.
Por otra parte, de la matriz de correlacin (la Tabla 8) de la capacidad que secreta la insulina contra descriptores
diferentes, se observ una co-linealidad alta entre pEC de los compuestos del juego de formacin y SR., HBA, CHI1,
PPSA1, WPSA2 y Sombreado, indicando el predominio de estos parmetros en descripcin de la capacidad que
secreta la insulina de los compuestos del juego de formacin. El modelo QSAR generado mostr la correlacin entre
pEC y estos descriptores diferentes (Eq. (3)). Las correlaciones de descriptores moleculares diferentes con la
capacidad que secreta la insulina se presentan en la Tabla 10. El modelo QSAR generado se represent grficamente
dispersando complots del experimental contra pEC de valores de capacidad predito que secreta la insulina
ya que el juego de formacin compone como mostrado en Fig. 15.