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The present investigation reports the design and synthesis of three series of benzoylthioureido derivatives bearing either benzenesulfonamide 7a–f, benzoic acid 8a–f or ethylbenzoate 9a–f moieties. The synthesised compounds were screened for their carbonic anhydrase inhibitory activity (CAI) against four isoforms hCA I, II, IX, and XII. Compounds 7a, 7b, 7c, and 7f exhibited a potent inhibitory activity towards hCAI (Kis = 58.20, 56.30, 33.00, and 43.00 nM), respectively compared to acetazolamide (AAZ) and SLC-0111 (Kis = 250.00 and 5080.00 nM). Compounds 7a, 7b, 7c, 7e, and 7f elicited selectivity over h CA II (Kis = 2.50, 2.10, 56.60,39.60 and 39.00 nM) respectively, relative to AAZ and SLC-0111(Kis = 12.10 and 960.00 nM). Also, compounds 7c, 7f, and 9e displayed selectivity against the tumour-associated isoform hCA IX (Kis = 31.20, 30.00 and 29.00 nM) respectively, compared to AAZ and SLC-0111 (Kis = 25.70 and 45.00 nM). Additionally, compounds 8a and 8f revealed a moderate to superior selectivity towards hCAXII (Kis = 17.00 and 11.00 nM) relative to AAZ and SLC-0111(Kis = 5.70 and 45.00 nM). Molecular docking and ADME prediction studies were performed on the most active compounds to shed light on their interaction with the hot spots of the active site of CA isoforms, in addition to prediction of their pharmacokinetic and physicochemical properties. [ABSTRACT FROM AUTHOR]

Aim: Due to emergence of resistance to available anticancer agents, there is a need to search for new cytotoxic agents. Methods: Pyrido[2,3- d ]pyrimidines ( 4 - 6 ) and their tricyclic derivatives ( 7-13 ) were prepared and screened for their cytotoxicity against breast MCF-7, prostate PC-3 and lung A-549 cancer cell lines as well as normal fibroblasts WI-38. Results: The most active compounds were 6b, 6e and 8d compared with doxorubicin. Moreover, compounds 6b and 8d induced apoptosis in PC-3 and MCF-7, respectively via activation of CASP3 (in PC-3 only), Bax, p53 and down regulation of Bcl2 in addition to CDK4/6 inhibition. Conclusion: Pyrido[2,3- d ]pyrimidine represents an important core for discovery of new potent cytotoxic agents acting on the cell cycle via apoptosis induction through either intrinsic or extrinsic pathways.

New imidazo[4,5-b]pyridine derivatives were designed, synthesized and screened for their anticancer activity against breast (MCF-7) and colon (HCT116) cancer cell lines. Nine compounds (I, II, IIIa, IIIb, IV, VI, VIIa, VIII, IX) showed significant activity against MCF-7, while six compounds (I, VIIc, VIIe, VIIf, VIII, IX) elicited a remarkable activity against HCT116. Compounds showing significant anticancer activity revealed remarkable CDK9 inhibitory potential (IC 50  = 0.63-1.32 μM) relative to sorafenib (IC 50  = 0.76 μM). Moreover, a molecular docking study was performed to illustrate the binding mode of the most active compounds in the active site of CDK9 where it revealed superior binding affinity relative to the natural ligand (T3C)., (Copyright © 2018 Elsevier Inc. All rights reserved.)