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New tilomisole-based benzimidazothiazole derivatives were designed and synthesized in this work. Their anti-inflammatory activity was assessed through the in vivo carrageenan rat paw edema model, and the in vitro COX inhibition assay. Compounds 13, 20, 30, 40, 43, and 46 demonstrated values of inhibition of induced edema in the in vivo assay comparable to celecoxib. All the synthesized compounds expressed their activity on COX-2 enzyme more than COX-1, proving their advantageous selectivity. In addition, compounds 13, 16, 20, 25, and 46 displayed lower IC 50 values than celecoxib as a reference drug against COX-2 enzyme; having values of 0.09, 13.87, 32.28, 33.01, and 5.18 nM respectively vs 40.00 nM for celecoxib. Particularly, the most active compound (13) with its extreme potency (400 folds more potent than celecoxib) exhibited a notable high selectivity index (SI = 159.5). In silico studies, including ADMET prediction, compliance to Lipinski's rule of five, and molecular docking into the active site of both COX isozymes were conducted for the synthesized compounds. The results suggested that these compounds are good candidates for orally active drugs, and docking revealed higher number of interactions with COX-2 for 13 as the most active compound compared with COX-1 reflecting its advantageous selectivity and explaining its extreme potency., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A series of 5-imino-4-thioxo-2-imidazolidinone derivatives with different substituents at N 1 and N 3 was synthesized with high yield and excellent purity by the reaction of different N-arylcyanothioformamide derivatives with isocyanate derivatives. Treatment 5-imino-4-thioxo-2-imidazolidinone derivatives with acidic medium afforded 4-thioxoimidazolidin-2,5-dione derivatives. The structures of the obtained products were established based on spectroscopic IR, 1 H NMR, 13 C NMR, 1 H, 1 H-COSY, HSQC and elemental analyses. The anti-inflammatory activity of the synthesized compounds through the carrageenan-paw edema model as well as in vitro COX-1 and COX-2 inhibition assay were evaluated where most of the synthesized compounds showed significant anti-inflammatory activity. Mostly, all of our synthesized compounds have greater activity more than celecoxib toward both cyclooxygenase enzymes. All of the tested compounds (except one compound) exhibited IC 50 valves for COX-2 ranged from 0.001 × 10 -3 to 0.827 × 10 -3  µM while the reference drug has IC 50 40.0 × 10 -3  µM. Furthermore, the analgesic activity of such compounds was also determined. Molecular modeling study was also conducted to rationalize the potential as anti-inflammatory agents of our synthesized compounds by predicting their binding modes, binding affinities and optimal orientation at the active site of the COX enzymes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A new series of benzimidazothiazole derivatives has been synthesized. The structure of the products was confirmed by spectroscopic techniques such as IR, NMR and mass spectroscopy. The tested compounds were evaluated for their anti-inflammatory activity either in vitro through the COX enzyme inhibition assay, or in vivo through carrageenan paw edema technique. Results revealed that compound 25 and 29 represented the most active ones among the entire series with % inhibition 72.19, 72.07 for COX-1, and 87.46, 87.38 for COX-2, respectively. Interestingly, all synthesized compounds exhibited IC 50 values less than both reference drugs celecoxib and naproxen, indicating their superior potency. For compound 25, it showed about 340 and 198 times more potent than celecoxib and naproxen respectively as COX-1 inhibitor (IC 50 value 0.044 vs. 15.000 and 8.700 µM), and 10 and 115 times more potent than the same drugs as COX-2 inhibitor (IC 50 value 4.52 vs. 40.00 and 520.00 nM). The antitumor activity of the products was also evaluated and the results obtained are consistent with those obtained by the anti-inflammatory screening where compounds 25 and 29 proved to be the most active ones among the other compounds with %GI ranging from 31.5 to 62.5% and they exhibited the lowest IC 50 values as well. The ADMET analysis of the tested compounds was also performed in addition to the molecular modeling studies that included flexible alignment, surface and electrostatic maps in addition to the Lipinisk's rule of five., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Tyrosine kinases are one of the most critical mediators in the signaling path way. Late studies have proved the part of tyrosine kinases in the pathophysiology of cancer diseases. This current research paper has focused on investigating the novel Pyrazolo[1,5-a]pyrimidines and Pyrido[2,3-d]pyrimidines as a small molecules that can inhibit tyrosine kinase in cancer cells. NCI protocol was applied to test the antitumor activity of such compounds. Leukemia and renal cancer cell lines proved to be sensitive to some derivatives such as 6b-d, 9a and 11 with GI% values ranging from 30.4 to 41.3%. In addition, compound 11 proved to be the most active against MCF-7 with GI% 62.5. The synthesized compounds were also evaluated for their inhibitory effects against EGFR kinase enzyme. Compound 9b proved to be the most active one among the synthesized series with inhibition % value of 81.72 at 25 nM concentration and IC 50 8.4 nM which is very close to the reference drug Sorafenib. In vitro cytotoxicity test was also performed using the MCF-7 breast cell line. Computer modeling using the active site of tyrosine kinase as a template and the most active tyrosine kinase inhibitors were calculated. Docking studies of the synthesized compounds into the active site of EGFR kinase domain showed good agreement with the obtained biological results., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Inflammation is a fundamental physiological process that is essential for survival of human being but at the same time is one of the major causes of human morbidity and mortality. In the past decade, numerous advances have taken place in the understanding and development of novel anti-inflammatory drugs. Therefore, investigation of newest anti-inflammatory agents is still a major challenge. In this study, novel and successfully synthesized naproxen-derivatives indicated powerful anti-inflammatory properties as potent of COX-1 and/or COX-2 inhibitors are reported. Results obtained revealed the presence of very potent derivatives with% inhibition of the oedema by 100% in addition to enzyme inhibition values that can reach 92%. The molecular docking and molecular dynamic calculations have been studied. Thus, new potent candidates for further investigation as prospective non-steroidal anti-inflammatory drug were proposed. Furthermore, twenty of the synthesized derivatives have been selected by the NCI, USA for anti-cancer screening and some of the tested compounds showed good% growth inhibition and some selectivity against some cell lines such as melanoma, non-small cell lung and colon cancer with GI% values ranging from 60.9 to 82.8%. Structure activity relationship has been performed and molecular modeling studies and molecular dynamic simulations have been performed for more explanation of the action of the synthesized compounds., (Copyright © 2017 Elsevier Inc. All rights reserved.)