Design, synthesis, in vitro and in vivo evaluation of novel pyrrolizine-based compounds with potential activity as cholinesterase inhibitors and anti-Alzheimer's agents.

Novel series of pyrrolizine based compounds (4-6 and 9-11) were designed, synthesized and evaluated as potential anti-Alzheimer agents. Most of the tested compounds showed selectivity to hAChE over hBChE and effectively inhibited self-induced amyloid beta aggregation in vitro. Among these derivatives, compound 10 displayed high selectivity towards hAChE (Ki = 1.47 ±â€¯0.63 µM for hAChE and Ki = 40.15 ±â€¯3.31 µM for hBChE). However, compound 11 displayed dual inhibitory effect against hAChE and hBChE at submicromolar range (Ki = 0.40 ±â€¯0.03 and 0.129 ±â€¯0.009 µM, respectively). Kinetic studies of the new ligands showed competitive type inhibition for both hAChE and hBChE. Moreover, compounds 10 and 11 showed lower or comparable cytotoxicity to donepezil against human neuroblastoma (SH-SY5Y) and normal human hepatic (THLE2) cell lines. In vivo studies confirmed that both compounds were able to improve cognitive dysfunction of scopolamine-induced AD mice. Finally, molecular docking simulation of compounds 10 and 11 in hAChE active site showed good agreement with the obtained pharmaco-biological results.

Synthesis and antitumor activity of pyrido [2,3-d]pyrimidine and pyrido[2,3-d] [1,2,4]triazolo[4,3-a]pyrimidine derivatives that induce apoptosis through G1 cell-cycle arrest.

New series of 2-(2-arylidenehydrazinyl)pyrido[2,3-d]pyrimidines 5a-e and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines 6-15 were synthesized and evaluated for their cytotoxic activity against two cancer cell lines, namely PC-3 prostate cancer and A-549 lung cancer. Some of the tested compounds displayed high growth inhibitory activity against PC-3 cells. Whereas, compounds 5b and 15f showed relatively potent antitumor activity against PC-3 and A-549 cell lines. In particular, 4-(3-acetyl-5-oxo-6-phenyl-8-(thiophen-2-yl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-1(5H)-yl)benzenesulfonamide 15f exhibited superior antitumor activity against both cell lines at submicromolar level (IC50 = 0.36, 0.41 µM, respectively). Moreover, the potential mechanisms of the cytotoxic activity of the promising compound 15f on the more sensitive cell line PC-3 were studied. The data indicated that 15f was able to cause cell cycle arrest at least partly through enhancing the expression level of the cell cycle inhibitor p21 and induced cancer cell apoptosis via caspase-3 dependent pathway.

Celecoxib analogs bearing benzofuran moiety as cyclooxygenase-2 inhibitors: design, synthesis and evaluation as potential anti-inflammatory agents.

Novel series of celecoxib analogs endowed with benzofuran moiety 3a-e and 9a-d were synthesized and evaluated for COX-1/COX-2 inhibitory activity in vitro. The most potent and selective COX-2 inhibitors - compounds 3c, 3d, 3e, 9c and 9d - were assessed for their anti-inflammatory activity and ulcerogenic liability in vivo. The 3-(pyridin-3-yl)pyrazole derivatives 3c and 3e exhibited the highest anti-inflammatory activity, that is equipotent to celecoxib. Furthermore, the tested compounds proved to have better gastric safety profile compared to celecoxib. In particular, compound 3e demonstrated about 40% reduction in ulcerogenic potential relative to the reference drug. Finally, molecular docking simulation of the new compounds in COX-2 active site and drug likeness studies showed good agreement with the obtained pharmaco-biological results.

Synthesis and bioactivity evaluation of new 6-aryl-5-cyano thiouracils as potential antimicrobial and anticancer agents.

Several novel 6-aryl-5-cyano thiouracil derivatives were synthesized and explored for their activities as antibacterial, antifungal and anticancer agents. The antimicrobial evaluation revealed that compounds 7b and 7c possessed superior antibacterial activity against the Gram positive bacteria S. aureus and B. subtilis compared to the reference drug amoxicillin. Moreover, compound 4i was found to be a broad spectrum antimicrobial agent and it also exhibited the highest antifungal activity against C. albicans, even higher than the reference drug amphotericin B (MIC = 2.34, 3.00 µg/mL respectively). Selected compounds were tested for in vitro cytotoxicity at a single 10(-5) M concentration in accordance to the NCI (USA) protocol. The preliminary screening results showed that most of the compounds had limited cytotoxic activity against renal cancer UO-31 and/or A498 cell lines. Nevertheless, compounds 6d and 6i displayed potent growth inhibitory effect toward non-small cell lung cancer HOP-92 and leukemia MOLT-4 cell lines, respectively.

Synthesis and in vitro cytotoxic activity of novel pyrazolo[3,4-d]pyrimidines and related pyrazole hydrazones toward breast adenocarcinoma MCF-7 cell line.

New series of pyrazolo[3,4-d]pyrimidines (7a-e and 13a-d) and pyrazole hydrazones 17a-d were synthesized and evaluated for their antiproliferative activity against human breast adenocarcinoma MCF-7 cell line. Most of the tested compounds exploited potent to moderate growth inhibitory activity, in particular compound 7e exhibited superior potency to the reference drug cisplatin (IC(50)=7.60 and 13.29 µM, respectively). The antitumor activity of the new compounds was accompanied by significant increase in the activity of superoxide dismutase with concomitant decrease in the activities of catalase and glutathione peroxidase and reduced glutathione level. Accordingly, the overproduction of hydrogen peroxide, nitric oxide and other free radicals allowed reactive oxygen species (ROS)-mediated tumor cells death, as monitored by reduction in the synthesis of protein and nucleic acids.

Novel diphenylamine 2,4'-dicarboxamide based azoles as potential epidermal growth factor receptor inhibitors: synthesis and biological activity.

Several hybrid molecules of diphenylamine-2,4'-dicarboxamide with various azolidinones and related heterocyclic rings have been synthesized and explored as epidermal growth factor receptor (EGFR) kinase inhibitors. Most of them displayed promising in vitro tyrosine kinase inhibition as well as potent cellular antiproliferative activity in the EGFR over-expressing breast cancer cell line (MCF-7). Compounds 12b and 13b that exhibited the highest inhibition in the kinase assay (89, 81% inhibition at 10 µM, respectively), showed potent antiproliferative effect against MCF-7 tumor cell line (IC(50) 1.04, 0.91 µM respectively). Molecular docking studies revealed that these compounds can bind to ATP binding site of the EGFR kinase domain and were involved in H-bonding with Met 793, in analogy to the known EGFR tyrosine kinase inhibitors. Moreover, compounds 15a-c possessed profound antitumor activity (IC(50) 0.59-0.73 µM) and significant EGFR-TK inhibition, making them of particular interest. In summary, the newly synthesized compounds provide promising new lead for the future design and development of anticancer agents of potential EGFR-TK inhibitory activity.

Molecular modeling study and synthesis of quinazolinone-arylpiperazine derivatives as α1-adrenoreceptor antagonists.

Three series of new 2-[(4-substituted piperazin-1-yl) methyl]quinazolin-4(3H)-ones 4a-c, Ethyl 6,7-dimethoxy-4-oxo-3-[2-(4-substituted piperazin-1-yl)acetamido/propanamido]-3,4-dihydroquinazoline-2-carboxylates 9a-f and their 2-methyl analogues 13a-l were designed and synthesized as promising α1-adrenoceptor antagonists. The final compounds were evaluated for their in vivo hypotensive activity in normotensive cats. The most potent hypotensive quinazolinone derivatives 4b, 9e, 13i, 13j were further tested on isolated thoracic aortic rings of male Wister rats. All the tested compounds displayed α1-blocking activity with IC50 ranging from 0.2 to 0.4 mM less than prazosin. Furthermore, in the present work, molecular modeling study using Accelrys Discovery Studio 2.1 software was performed by mapping the synthesized compounds to the α1-adrenoceptor antagonist hypothesis in order to predict their mechanism of action. Compound 13j which has the best-fitting score displayed the highest in vivo and in vitro activity among the tested compounds.

Synthesis and biological evaluation of novel 2,4'-bis substituted diphenylamines as anticancer agents and potential epidermal growth factor receptor tyrosine kinase inhibitors.

Four new series of 2,4'-bis diphenylamine hydrazones 14, 2,4'-bis aminothiadiazole 16, 2,4'-bis mercaptotriazole 17-18 and 2,4'-bis mercapto-oxadiazole diphenylamine derivatives 19-20 were synthesized and evaluated for their ability to inhibit EGFR tyrosine kinase. Compound N-ethyl-5-{2-[4-(5-(ethylamino)-1,3,4-thiadiazol-2-yl)- phenylamino]phenyl}-1,3,4-thiadiazol-2-amine 16a was the most active enzyme inhibitor (98% inhibition at 10 microM). Moreover, all compounds that showed enzyme inhibition activity were tested in vitro on human breast carcinoma cell line (MCF-7) in which EGFR is highly expressed. The tested compounds exploited potent antitumor activity with IC(50) values ranging 0.73-2.38 microM. Molecular modeling and docking of the synthesized compounds into the active site of EGFR kinase domain showed good agreement with the obtained biological results. The present work represents a novel class of diphenylamine based derivatives with potent cytotoxicity and promising EGFR PTK inhibition activity.