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Page 2 of 26 RSC Advances RSC Advances Accepted ManuscriptConsidering potent cytotoxic activities of hybrid benzofuran-imidazolium and quinazolinone derivatives on breast cancer cell line (MCF-7), novel hybrid derivatives incorporating benzofuran, imidazole and quinazolinone pharmacophores were designed by molecular hybridization approach. Since aromatase is highly expressed in MCF-7 cell line, we tried to put these pharmacophores together in such a way to arrange themselves in a symmetrical shape, similar to aromatase inhibitors. Subsequently, the binding of these novel hybrid compounds to aromatase have been investigated in a docking procedure applying a combined quantum mechanical/molecular mechanical (QM/MM) method. The QM/MM calculation was performed on the reference structures, to obtain atomic charges on the ligand atoms. The results indicated that hybrid compounds adopted properly within the aromatase binding site, suggesting that they could be potential inhibitors of aromatase. These novel designed compounds engage in hydrophobic and H bond interactions with the aromatase binding site, which are in agreement with the basic physicochemical features of known aromatase inhibitors. To obtain more accurate results for the binding energies of ligands, the structures of ligands with the best interaction energy, obtained from docking study, were re-optimized by three-layer ONIOM method (QM:QM:MM) in which the binding pocket of the enzyme was considered as a medium-level. The results demonstrated that when the optimized geometrical structures were subjected for re-docking, better interaction energy was obtained which strengthen the ability of these compounds as potential inhibitors of aromatase.

4-Sulfonamide substituted benzamidobenzimidazolones were designed and docked into the active site model of CDK2, using an oxindole inhibitor as the template. Compounds 6a-6i were then prepared from the reaction of the sulfonyl chloride 1 with different amines to give the corresponding acids (2a-2i), which were converted to their corresponding acyl chlorides (3a-3i). Reaction of 3a-3i with o-nitrophenylhydrazine afforded the respective nitro derivatives (4a-4i). The nitro groups were then reduced to give the corresponding amines (5a-5i), which, upon reaction with ethyl chloroformate, the target compounds (6a-6i) were produced. Target benzimidazolone derivatives (9a-9e) were also prepared from the reaction of isopropenyl benzimidazolone (8) with different sulfonyl or acyl chlorides. The target compounds were then tested by a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against the cancer cell lines, Hep G2, HT-29, CL1-5 and AGS. Despite similar binding properties of the flexible benzamidobenzimidazolones and rigid cytotoxic oxindole inhibitors at the active site of CDK2, biological screening results indicated that benzamidobenzimidazolones did not exhibit significant cell growth inhibition in vitro. Their analogue, 3-acyl benzimidazolone (12), however, revealed cytotoxicity similar to that of the reference oxindole inhibitor.

The present study was planned to design some novel aldimine-type Schiff bases bearing 3,4,5-trimethoxyphenyl and 1,2,4-triazole-3-thione/thiol as potential tubulin polymerization inhibitors. The obtained results of the molecular docking study using the tubulin complex (PDB code: 1SA0) showed that compounds H-25 and H-26 were well fitted in the colchicine binding site of tubulin with binding energies of -8.68 and -8.40 kcal/mol, respectively, in comparison to the main ligand (-8.20 kcal/mol). In parallel, molecular simulations were also performed on five other 3,4,5-trimethoxyphenyl-containing ligand targets including hsp90, VEGFR2, and human and microbial (Staphylococcus aureus and Candida albicans) dihydrofolate reductase, among which H-17, H-45, H-27, H-02, and H-19 were the most suitable compounds, respectively. Evaluation of the cytotoxic effect of the most efficient compounds of the docking steps (H-25) revealed IC50 values of 12.48 ± 1.10, 4.25 ± 0.22, 3.33 ± 0.31, and 9.71 ± 0.75 µM against the HT1080, HT29, MCF-7, and A549 cell lines, respectively, compared to doxorubicin (12.69 ± 1.23, 6.12 ± 0.47, 3.51 ± 0.32, and 6.40 ± 0.31 µM, respectively). The in vitro tubulin polymerization investigation launched compounds H-25 and H-26 as potent antitubulin agents due to their IC50 values of 0.17 ± 0.01 and 10.93 ± 0.43 µM, respectively.

Syntheses of (±)-cis-3-hydroxycarbonyl-7-(phenylacetamido)carbacephem (10 ), (±)-cis-3-methoxycarbonyl-7-(phenylacetamido)carbacephem (11 ), (±)-cis-2-chloro-3-hydroxycarbonyl-7-(phenylacetamido)carbacephem (14 ), and (±)-cis-2-chloro-3-methoxycarbonyl-7-(phenylacetamido)carbacephem (15 ) were accomplished. These four heretofore undescribed compounds 10 , 11 , 14 , and 15 showed notable activity against Staphylococcus aureus FDA 209P, Escherichia coli ATCC 39188, Pseudomonas aeruginosa 1101-75, Klebsiella pneumoniae NCTC 418 as well as the β-lactamase producing organisms E. coli A9675, P. aeruginosa 18S-H and methicillin-resistant organism S. aureus 95. The electronic activation of lactam moieties of 11 and 15 enhanced remarkably their antibacterial activity relative to those of the 10 and 14 . The chlorine atom in 14 and 15 , acting as an effective leaving group, also resulted in an increment in the biological activity in comparison with those of the parent carbacephemes 10 and 11 . The mode of action related to 14 and 15 can be explained by a non-classical [1,4]-elimination process.