Design and prediction of new anticoagulants as a selective Factor IXa inhibitor via three-dimensional quantitative structure-property relationships of amidinobenzothiophene derivatives.

Factor IXa (FIXa), a blood coagulation factor, is specifically inhibited at the initiation stage of the coagulation cascade, promising an excellent approach for developing selective and safe anticoagulants. Eighty-four amidinobenzothiophene antithrombotic derivatives targeting FIXa were selected to establish three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models using comparative molecular field analysis and comparative similarity indices analysis methods. Internal and external cross-validation techniques were investigated as well as region focusing and bootstrapping. The satisfactory q (2) values of 0.753 and 0.770, and r (2) values of 0.940 and 0.965 for 3D-QSAR and 3D-QSSR, respectively, indicated that the models are available to predict both the inhibitory activity and selectivity on FIXa against Factor Xa, the activated status of Factor X. This work revealed that the steric, hydrophobic, and H-bond factors should appropriately be taken into account in future rational design, especially the modifications at the 2'-position of the benzene and the 6-position of the benzothiophene in the R group, providing helpful clues to design more active and selective FIXa inhibitors for the treatment of thrombosis. On the basis of the three-dimensional quantitative structure-property relationships, 16 new potent molecules have been designed and are predicted to be more active and selective than Compound 33, which has the best activity as reported in the literature.

Diphenyl ethers from Aspergillus sp. and their anti-Aß42 aggregation activities.

Two new compounds with the character of diphenyl ether structure, oxisterigmatocystin D (1) and 9-acetyldiorcinol B (6), were isolated from the endolichenic fungal strain Aspergillus sp. (No. 16-20-8-1), along with six known compounds, oxisterigmatocystin A (2), oxisterigmatocystin C (3), sterigmatocystin (4), diorcinol B (5), violaceol-I (7), and violaceol-II (8). The structures of the new compounds were determined by extensive NMR spectroscopic data, and the absolute configuration of 1 was established by single-crystal X-ray diffraction analysis. Moreover, the Aß42 aggregation inhibitory activities of 5-8 were evaluated by the standard thioflavin T (ThT) fluorescence assay using epigallocatechin gallate (EGCG) as the positive control. Compounds 7 and 8 displayed significant anti-Aß42 aggregation activity with IC50 values of 5.1 and 2.3µM, respectively. Preliminary structure-activity relationship of these diphenyl ethers as anti-Aß42 aggregation inhibitors was proposed.