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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]

This investigation describes the design of a series of cycloheptathieno[2,3-d]pyrimidines along with their synthetic strategy. The target compounds were screened for their PARP-1 inhibitory activity. The modeling study declared that most of the docked compounds showed the same interactions as 3-aminobenzamide, where Gly 894, His 862, Tyr 896, Arg 878, and Ser 864 were the main residues involved in hydrogen bond formation. Compounds eliciting the top ranked docking results were screened for their PARP-1 inhibitory activity giving promising results, and three representative compounds were tested for their cytotoxic activity using Doxorubicin as a reference standard. The target compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 including cyclohepta[b]thiophene and pentahydrocycloheptathieno[2,3-d]pyrimidine cores were designed, prepared, and tested for their PARP-1 inhibitory activity. Compounds 16 (R: -NHC(S)NH2) and 11 (R: -CS) were the most potent ones. [ABSTRACT FROM AUTHOR]

Four series of some 4-substituted-1-phenyl-1 H-pyrazolo[3,4- d]pyrimidine derivatives 5a- f, 6a- f, 8a- f, and 9a- f were designed to be screened for their antitumor activity. All compounds were evaluated against breast ( MCF-7) and lung ( A-549) cell lines. Six compounds 5a, 5b, 6b, 6e, 9e, and 9f displaying activity against both cell lines were further estimated for their EGFR- TK inhibitory activity where they revealed 41-91% inhibition and compound 6b elicited the highest activity (91%). A docking study of these compounds into the ATP-binding site of EGFR- TK demonstrated their binding mode where H-bonding interaction with Met793 through N1 of pyrimidine or N2 of pyrazole was observed. [ABSTRACT FROM AUTHOR]

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. [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.)