Design, synthesis, and antitumor screening of new thiazole, thiazolopyrimidine, and thiazolotriazine derivatives as potent inhibitors of VEGFR-2.

New thiazole, thiazolopyrimidine, and thiazolotriazine derivatives 3-12 and 14a-f were synthesized. The newly synthesized analogs were tested for in vitro antitumor activity against HepG2, HCT-116, MCF-7, HeP-2, and Hela cancer cells. Results indicated that compound 5 displayed the highest potency toward the tested cancer cells. Compound 11b possessed enhanced effectiveness over MCF-7, HepG2, HCT-116, and Hela cancer cells. In addition, compounds 4 and 6 showed promising activity toward HCT-116, MCF-7, and Hela cancer cells and eminent activity against HepG2 and HeP-2 cells. Moreover, compounds 3-6 and 11b were tested for their capability to inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) activity. The obtained results showed that compound 5 displayed significant inhibitory activity against VEGFR-2 (half-maximal inhibitory concentration [IC50 ] = 0.044 µM) comparable to sunitinib (IC50 = 0.100 µM). Also, the synthesized compounds 3-6 and 11b were subjected to in vitro cytotoxicity tests over WI38 and WISH normal cells. It was found that the five tested compounds displayed significantly lower cytotoxicity than doxorubicin toward normal cell lines. Cell cycle analysis proved that compound 5 induces cell cycle arrest in the S phase for HCT-116 and Hela cancer cell lines and in the G2/M phase for the MCF-7 cancer cell line. Moreover, compound 5 induced cancer cell death through apoptosis accompanied by a high ratio of BAX/BCL-2 in the screened cancer cells. Furthermore, docking results revealed that compound 5 showed the essential interaction bonds with VEGFR-2, which agreed with in vitro enzyme assay results. In silico studies showed that most of the analyzed compounds complied with the requirements of good oral bioavailability with minimal toxicity threats in humans.

Synthesis and Molecular Docking Study of New Thiazole Derivatives as Potential Tubulin Polymerization Inhibitors.

A new series of 2,4-disubstituted thiazole derivatives containing 4-(3,4,5-trimethoxyphenyl) moiety was synthesized and evaluated for their potential anticancer activity as tubulin polymerization inhibitors. All designed compounds were screened for cytotoxic activity against four human cancer cell lines, namely, HepG2, MCF-7, HCT116, and HeLa, using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, with combretastatin A-4 as a reference drug. Compounds 5c, 6d, 7c, 8, and 9a,b showed superior activity against the tested cell lines, with IC50 values ranging from 3.35 ± 0.2 to 18.69 ± 0.9 µM. Further investigation for the most active cytotoxic agents as tubulin polymerization inhibitors was also performed in order to explore the mechanism of their antiproliferative activity. The obtained results suggested that compounds 5c, 7c, and 9a remarkably inhibit tubulin polymerization, with IC50 values of 2.95 ± 0.18, 2.00 ± 0.12, and 2.38 ± 0.14 µM, respectively, which exceeded that of the reference drug combretastatin A-4 (IC50 2.96 ± 0.18 µM). Molecular docking studies were also conducted to investigate the possible binding interactions between the targeted compounds and the tubulin active site. The interpretation of the results showed clearly that compounds 7c and 9a were identified as the most potent tubulin polymerization inhibitors with promising cytotoxic activity and excellent binding mode in the docking study.

Synthesis, biological evaluation, and molecular modeling simulations of new heterocyclic hybrids as multi-targeted anti-Alzheimer's agents.

The widespread and the recognition of the multifactorial nature of Alzheimer disease (AD) increased the demands for multi-targeted directed ligands (MTDLs) to overcome possible drug-drug interactions of the combination therapy, and to acquire superior therapeutic profile than single targeted molecules. Two main scaffolds namely: pyrazolopyridine and tetrahydroacridine (THA) were used to synthesize four different series of integrated multi-targeted synthons possessing ChE (hAChE or hBuChE), Aß1-42 aggregation inhibition potency, in addition to optimum metal chelating capability. Structure modifications were performed to 9-amino function of THA core of tacrine and the pyrazolopyridine scaffolds linked to a variety of cyclic secondary amines directly or using amide spacers or ethylamine bridge or engaging THA with pyrazolopyridine to produce hybrid compounds. Different 9-amino substitutions improved the in vitro hAChE activity of 7- or 6,7-disubstituted THA derivatives. Compounds 16 and 28 proved to be multimodal anti-AD agents as they were potent hAChE inhibitors, in addition, they could bind with the amino acids of the peripheral anionic site (PAS) affecting Aß aggregation and hence Aß-dependent neurotoxicity especially compound 16 which was almost twofold more active than donepezil. Furthermore, both compounds directly inhibited Aß1-42 self-aggregation and chelated bio-metals such as Fe2+, Zn2+ and Cu2+ preventing reactive oxygen species (ROS) generation by Aß and its oxidative damage in the brain regions of AD patients. Compound 28 had superior privilege by its dual ChE activity resulting in better cognitive improvement. Compounds 16 and 28 showed acceptable relative safety upon hepG2 cell line and excellent BBB penetration with wide safety margin as their LD50 were higher than 120 mg/kg.

Synthesis, in vivo anti-inflammatory, COX-1/COX-2 and 5-LOX inhibitory activities of new 2,3,4-trisubstituted thiophene derivatives.

New series of thiophene derivatives were synthesized and evaluated for their in vivo anti-inflammatory activity using carrageenan-induced paw edema model. The most active in vivo anti-inflammatory compounds 5b, 11b, 14c, 18c, 19c and 20d were further evaluated for their in vitro COX-1/COX-2 and 5-LOX inhibitory activities. The in vitro assay results revealed that the N-(4-(4-chlorophenyl)-3-cyanothiophen-2-yl)-2-morpholinoacetamide (5b) possesses the highest selectivity toward COX-2 (IC50 = 5.45 µM) with selectivity index value of 8.37 compared to celecoxib with COX-2 selectivity index value of 15.44. In addition, it showed acceptable 5-LOX inhibitory activity (IC50 = 4.33 µM) compared to NDGA (IC50 = 2.46 µM). Molecular modeling study was conducted to study the postulated binding of compound 5b into the active site of COX-2 and 5-LOX, and it revealed that 5b binds similarly to celecoxib and NDGA, respectively. Overall, the morpholinoacetamide-thiophene hybrid 5b could serve as a promising lead for further development of new potent anti-inflammatory agents that act as dual COX-2/5-LOX inhibitors.

Synthesis and biological screening of new thiazolo[4,5-d]pyrimidine and dithiazolo[3,2-a:5',4'-e]pyrimidinone derivatives as antimicrobial, antiquorum-sensing and antitumor agents.

New thiazolopyrimidine and dithiazolopyrimidinone derivatives 2-11 were synthesized and estimated for antimicrobial activity against S. aureus, B. cereus, E. coli, C. albicans, A. fumigatus and A. terreus. The attained results proved that 4, 8a and 11g have significant effectiveness against S. aureus and B. cereus. On the other hand, 7, 10b, 10c and 11h exhibited prominent activity against B. cereus, whereas 8a, 10b and 11g were proved to be active against E. coli. From another point of view, 4 and 8a exhibited promising efficacy against A. fumigatus and A. terreus; moreover, 8a showed outstanding efficacy against C. albicans. Quorum-sensing inhibitory activity of the new compounds was esteemed against C. violaceum, where 7, 8a, 9b, 10a-c, 11d and 11g have acceptable efficacy. In vitro antitumor efficacy of the same compounds against HepG2, HCT-116 and MCF-7 cancer cell lines was also tested. Compounds 4 and 11h showed enhanced effectiveness against the three cell lines, whereas 10b displayed eminent activity against HCT-116 and MCF-7 cells. Moreover, 11a was found to have outstanding activity against MCF-7 cells, while 11i showed promising efficacy against HepG2 cells. The in vitro active antitumor compounds were evaluated for in vivo antitumor effectiveness against EAC in mice, as well as in vitro cytotoxicity against WI38 and WISH normal cells. Results manifested that 4 has the strongest in vivo activity, and that all investigated analogs are less cytotoxic than 5-FU against both normal cell lines. DNA-binding affinity of the active compounds was examined, where 4, 8a, 10c, 11d and 11g,h displayed strong affinity. In silico studies proved that majority of the analyzed compounds are in conformity with the optimum needs for good oral absorption.

Synthesis, anti-inflammatory, analgesic, COX-1/2 inhibition activities and molecular docking study of pyrazoline derivatives.

Design, synthesis and pharmacological activities of a group of 1,3,5-trisubstituted pyrazolines were reported. The chemical structures of the synthesized compounds have been assigned on the basis of IR, MS, (1)H NMR, and (13)C NMR spectral analyses. The synthesized 1,3,5-trisubstituted pyrazoline derivatives were evaluated in vivo for anti-inflammatory, analgesic activities and in vitro for COX-1/2 inhibition assay. Among the tested compounds, derivatives 4h, 6e, 7a, 7e, and 9 showed more potent anti-inflammatory and analgesic activities than the reference drug celecoxib. On the basis of their higher activities in the in vivo studies compared with celecoxib, the five compounds 4h, 6e, 7a, 7e and 9 were selected to test their inhibitory activities against ovine COX-1/2 using an in vitro cyclooxygenase inhibition assay. Docking study of compounds 7a, 7e and 9 into the COX-2 binding site revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Synthesis and biological evaluation of new curcumin analogues as antioxidant and antitumor agents: molecular modeling study.

New curcumin analogues have been synthesized and their antioxidant activities were investigated by measuring their free radical scavenging capacities. The in vitro and in vivo antitumor activities of the synthesized compounds on Ehrlich ascites carcinoma (EAC) cell line were evaluated. 4-(4-Chlorophenyl)-2-(5-ethyl-7-(4-methoxybenzylidene)-3-(4-methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c] pyridin-2-yl)thiazole 7h showed excellent antineoplastic activity in both in vitro and in vivo studies more than that of tested compounds and reference drug, cisplatin. Different molecular modeling studies were performed, where docking of compound 7h into telomerase active site suggested that it could exert its antitumor potential by telomerase inhibition.

Synthesis and anti-inflammatory activity of novel (substituted)benzylidene acetone oxime ether derivatives: molecular modeling study.

Herein, we report the design, synthesis, and pharmacological properties of a series of substituted benzylidene acetone oxime ether derivatives from the corresponding oxime derivatives. All the newly synthesized compounds were investigated in vivo for their anti-inflammatory activities using carrageenin-induced rat paw oedema model. Among the compounds examined, compounds 5b and 7a showed the highest activity, nearly equivalent to that of the standard drug diclofenac sodium. Hence, they were screened for their analgesic activities using acetic acid-induced writhing model in mice and also, their ulcerogenic effects were studied. Compound 7a was found to possess significant anti-inflammatory and analgesic activities with negligible ulcerogenic effect. Docking study of the synthesized compound 7a into the active site of COX-1 and COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.