2-Phenylquinazolin-4(3H)-one scaffold as newly designed, synthesized VEGFR-2 allosteric inhibitors with potent cytotoxicity through apoptosis.

New derivatives of 2-phenylquinazolin-4(3H)-one were designed, synthesized, and biologically evaluated as potent allosteric kinase inhibitors with in situ cytotoxicity against MCF-7 and HepG2 cells. Compounds 15 and 18 among the proposed compounds showed promising antiproliferative activity against MCF-7 (IC50 = 1.35 µM) and HepG2 cells (IC50 = 3.24 µM), comparable to sorafenib, with IC50 values of 3.04, 2.93 µM, respectively, according to in situ cytotoxicity testing. Comparing compounds 15 and 18 to sorafenib, the in vitro VEGFR-2 inhibitory activity displayed encouraging selective efficacy with IC50 values of 13, 67, and 30 nM, respectively. Results of VEGFR-2 inhibition at various ATP concentrations proved that there was no statistically significant difference between the IC50 values, which improved the non-ATP competitive binding. Compound 15 caused apoptotic breast cancer cell death with 55.11-fold cell-cycle arrest at the S-phase, where it affected the apoptosis-mediated genes through upregulating P53, Bax, caspases 3, 8, and 9 and downregulating the antiapoptotic gene Bcl-2. A molecular docking study was conducted to confirm the binding of the designed compounds to the allosteric site of VEGFR-2 in DFG-out mode, leaving the ATP-binding pocket unoccupied when superimposed to the pose of sorafenib. The designed molecules showed resealable binding affinity toward the DFG loop and the allosteric site. Hence, the 2-phenylquinazolin-4(3H)-one derivative constitutes intriguing starting points for designing apoptotic-inducing drugs.

Anti-cancer activity of two novel heterocyclic compounds through modulation of VEGFR and miR-122 in mice bearing Ehrlich ascites carcinoma.

Metastasis in breast cancer is a leading cause of mortality among women in many countries. This study investigated the anti-cancer role of benzoimidazoquinazoline and benzimidazotriazin; two novel compounds that were designed, synthesized, structurally elucidated, and biologically evaluated as potent anti-angiogenic agents that act through inhibition of vascular endothelial growth factor receptor-2 (VEGFR2). Breast cancer was induced by inoculation of Ehrlich Ascites Carcinoma (EAC) cells. Seventy swiss albino mice were randomly divided into 7 groups, 10 animals each: (1) normal, (2) control EAC group, (3) cisplatin treated group, (4&5) benzoimidazoquinazoline treated (5 mg/kg and 10 mg/kg), (6&7) benzimidazotriazin treated (5 mg/kg and 10 mg/kg). The expression of miR-122 was assessed in the tumor tissue by quantitative PCR, and the VEGF level was determined in serum by ELISA. VEGFR2 and cluster of differentiation (CD)34 were assessed by immunohistochemistry. Serum ALT, AST, creatinine, and urea were measured. Treatment with benzoimidazoquinazoline and benzimidazotriazin decreased tumor weight and serum levels of VEGF, and down-regulated expression of VEGFR2 and CD34 in the tumor tissue. miR-122 was upregulated, particularly in the benzimidazotriazin (10 mg/kg) group. Relative to cisplatin, the novel compounds were less toxic to kidneys. Benzoimidazoquinazoline and benzimidazotriazin are promising anti-cancer agents that act through inhibition of angiogenesis and thus provide a new strategy for advancement of chemotherapy.

Toward a treatment of diabesity: Rational design, synthesis and biological evaluation of benzene-sulfonamide derivatives as a new class of PTP-1B inhibitors.

Targeting of protein tyrosine phosphatase-1B (PTP1B) has emerged as a promising strategy for therapeutic intervention of diabetes and obesity. Investigation of new inhibitors with good bioavailability and high selectivity is the major challenge of drug discovery program targeting PTP1B. Therefore, herein, new neutral benzene-sulfonamide containing compounds were designed, synthesized and biologically evaluated as potent PTP1B inhibitors. New series of thiazolidine, oxazolidine, thiazinan, oxazinan, oxazole, thiazole, tetrazole, cyanopyridine, chromenone, and iminochromene of benzene-sulfonamide derivatives (MSE-1 to MSE-15) were synthesized in a good yield under mild condition using sulfadiazine as a starting material. Among the synthesized compounds, MSE-13 and MSE-14 showed the most in vitro potent PTP-1B inhibitory activity (IC50 of 0.88 µM and 3.33 µM, respectively). Animal treatment by the target compounds significantly improved the insulin resistance, diminished plasma glucose level, decreased initial body weight, and normalized the serum lipid profile compared to pioglitazone, a standard PTP1B inhibitor. The molecular modeling study showed a high affinity and selectivity of our synthesized compounds to the active site and B-site of PTP1B holding hydrogen bonding, hydrophobic, and electrostatic interactions. Furthermore, Electrostatic Surface Potential (ESP) and HOMO/LUMO analysis indicated the importance of sulfamoyl moiety for PTP1B binding. In silico ADME predictions of such compounds also showed the promising pharmacokinetic and physicochemical properties. The proposed compounds could be considered a lead inhibitory scaffold to PTP1B.

Novel pyrazoles and pyrazolo[1,2-a]pyridazines as selective COX-2 inhibitors; Ultrasound-assisted synthesis, biological evaluation, and DFT calculations.

COX-2 is an inducible enzyme mediating inflammatory responses. Selective targeting of COX-2 is useful for developing anti-inflammatory agents devoid of ulcerogenic activity. Herein, we report the design and synthesis of a series of pyrazoles and pyrazolo[1,2-a]pyridazines with selective COX-2 inhibitory activity and in vivo anti-inflammatory effect. Both series were accessed through acid-catalyzed ultrasound-assisted reactions. The most active compounds in this study are two novel molecules, 11 and 16, showing promising selectivity and decent IC50 of 16.2 and 20.1nM, respectively. These compounds were also docked into the crystal structure of COX-2 enzyme (PDB ID: 3LN1) to understand their mode of binding. Finally, Mulliken charges and electrostatic surface potential were calculated for both compound 11 and celecoxib using DFT method to get insights into the molecular determinants of activity of this compound. These results could lead to the development of novel COX-2 inhibitors with improved selectivity.

Synthesis, molecular modelling, and preliminary anticonvulsant activity evaluation of novel naphthalen-2-yl acetate and 1,6-dithia-4,9-diazaspiro [4.4] nonane-3,8-dione derivatives.

The synthesis, pharmacological evaluation and molecular modelling study of novel naphthalen-2-yl acetate and 1,6-dithia-4,9-diazaspiro [4.4]nonane-3,8-dione derivatives as potential anticonvulsant agents are described. The newly synthesized compounds were characterized by both analytical and spectral data. Alkylation of 1H-imidazole or substituted piperazine with 1-(2-naphthyl)-2-bromoethanone (2) gave naphthalen-2-yl 2-(1H-imidazol-1-yl) acetate (3) and naphthalen-2-yl 2-(substituted piperazin-1-yl) acetate (4-8). Moreover, condensation of naphthalen-2-yl 2-bromoacetate or 2-bromo-1-(naphthalen-2-yl) ethanone with hydrazine hydrate and acetylacetone resulted in the formation of the cyclic pyrazole products 9 and 13. Sonication of naphthalen-2-yl acetate (1) with 2-chloropyridine, 2-chloropyrimidine and 2-(chloromethyl) oxirane gave naphthalen-2-yl 2-(pyridin-2-yl) acetate (10), naphthalen-2-yl 2-(pyrimidin-2-yl) acetate (11) and naphthalen-2-yl-3-(oxiran-2-yl) propanoate (12) respectively. Cyclocondensation reaction of 2-iminothiazolidin-4-one (14) with thioglycolic acid, thiolactic acid and thiomalic acid gave 1,6-dithia-4,9-diazaspiro [4.4]nonane-3,8-dione derivatives (15-17). The compounds were testedin vivofor the anticonvulsant activity by delaying strychnine-induced seizures. The diazaspirononane (17) and 1-(2-naphthyl)-2-bromoethanone (2) showed a high significant delay in the onset of convulsion and prolongation of survival time compared to phenobarbital. The molecular modelling study of anticonvulsant activity of synthesized compounds showed a CNS depressant activity via modulation of benzodiazepine allosteric site in GABA-A receptors.

Synthesis and biological activity of functionalized indole-2-carboxylates, triazino- and pyridazino-indoles.

Condensation of aryl hydrazines with ethyl pyruvate gave the respective hydrazones 4-6; Fischer indolization led to substituted-1H-indole-2-carboxylic acid ethyl esters 7-9. The Mannich reaction of these compounds with formaldehyde and morpholine yielded ethyl 3-(morpholinomethyl)-substituted-1H-indole-2-carboxylates 10-12. The 5,7-dichloro-1H-indole-2-carbohydrazide 13 was cyclized with methyl orthoformate in DMF to give 6,8-dichloro[1,2,4]triazino[4,5-a]indol-1(2H)-one 14. Vilsmeier-Haack formylation of 7-9 gave ethyl 3-formyl-substituted-1H-indole-2-carboxylates 15-17 whose 2,2'-((5-chloro-2-(ethoxycarbonyl)-1H-indol-3-yl)methylene)bis-(sulfanediyl) diacetic acid 18 was prepared. The reaction of 15 and 16 with substituted anilines by conventional and microwave methods gave ethyl 3-(N-aryliminomethyl)-5-halo-1H-indole-2-carboxylates 19-29. In a cyclocondensation reaction of 19-25 with thiolactic acid or thioglycolic acid substituted indolylthiazolidinones 30-33 were prepared. Reaction of hydrazine hydrate with 15-17 did not give the respective hydrazones but directly led to the cyclized products substituted-3H-pyridazino[4,5-b]indol-4(5H)-ones 34-36, while a reaction with 2,4-dichlorophenylhydrazine yielded the uncyclized hydrazones. The chlorination of 35 and 36 with POCl3 gave pyridazino[4,5-b]indoles 39 and 40, respectively; reaction of the latter compounds with morpholine gave 4-(substituted-5H-pyridazino[4,5-b]indol-4-yl)morpholine 41 and 42. Mannich reaction of 34 with formaldehyde and N-ethylpiperazine gave 8-chloro-3-((4-ethylpiperazin-1-yl)methyl)-3H-pyridazino[4,5-b]indol-4(5H)-one 43. The microwave assistance of selected reactions has a profound effect on the reaction speed. The structures of the new compounds were confirmed by both analytical and spectral data. Some compounds were subjected to investigations concerning their antimicrobial, tranquilizing, and anticonvulsant activities.