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A series of novel tetrahydropyrazolopyridone derivatives containing 1,3,4-triazole, triazolylmethyl, and partially saturated heterocyclic moieties as P2 binding element was designed, synthesized, and evaluated in vitro for anticoagulant activity in human and rabbit plasma. All compounds showed moderate to significant potency, and compounds 15b , 15c , 20b , 20c , and 22b were further examined for their inhibitory activity against human FXa in vitro. While compounds 15c and 22b were tested for rat venous thrombosis in vivo. The most promising compound 15c , with an IC 50 (FXa) value of 0.14 μM and 98% inhibition rate, warranted further investigation as an FXa inhibitor. [ABSTRACT FROM AUTHOR]

A series of novel 4,6-diphenyl-2-(1 H -pyrrol-1-yl)nicotinonitrile analogues of crolibulin and combretastatin A-4 (CA-4) were discovered using a 2-(1 H -pyrrol-1-yl)pyridine ring as link-bridge to retain the cis -orientations of A-ring and B-ring. All the target compounds were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines. Compounds 6a–d exhibited superior potency, with IC 50 values at nanomolar levels. In particular, compound 6a exhibited antitumor activity similar to or higher than crolibulin and CA-4. Moreover, the inhibition of microtubule assembly by compound 6a was comparable to that by CA-4. A molecular modeling study of compound 6a was performed to elucidate its binding mode at the colchicine binding site in the tubulin dimer, which also provided a basis for further structure-guided design of novel colchicine binding site inhibitors. [ABSTRACT FROM AUTHOR]