Discovery and optimization of 1,3,4-trisubstituted-pyrazolone derivatives as novel, potent, and nonsteroidal farnesoid X receptor (FXR) selective antagonists.

LBVS of 12480 in-house compounds, followed by HTRF assay, resulted in one nonsteroidal compound (11) with antagonistic activity against FXR (69.01 ± 11.75 µM). On the basis of 11, 26 new derivatives (12a-z) were designed and synthesized accordingly. Five derivatives (12f-g, 12p, 12u, and 12y) showed better antagonistic activities against FXR than compound 11. Remarkably, the most potent derivative, 12u (8.96 ± 3.62 µM), showed antagonistic capability approximately 10 times and 8-fold higher than that of the control (GS) and the starting compound 11, respectively. 12u was further confirmed to have high binding affinity with FXRαLBD, FXR specificity over six other nuclear receptors, and potent antagonistic activity against FXR in two cell testing platforms. 12u strongly suppressed the regulating effects of CDCA on FXR target genes. The therapeutic potential of 12u was identified by lowering the contents of triglyceride and cholesterol in human hepatoma HepG2 cells and in the cholesterol-fed C57BL/6 mices.

Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent.

Resistance of malaria parasites has quickly developed to almost all used antimalarial drugs. Accordingly, the discovery of new effective drugs to counter the spread of malaria parasites that are resistant to existing agents, especially acting on multi-targets, is an urgent need. The cysteine protease falcipain-2 (FP-2) and dihydrofolate reductase (DHFR) play crucial roles in the Plasmodium life cycle. In this study, a series of first-gereration small molecular dual inhibitor of FP-2 and DHFR have been designed and synthesized based on the lead compound 1, which was randomly identified by screening FP-2 inhibitors in our laboratory. Six compounds (2f-g, 2j, and 2m-o) showed improved dual inhibitory activities against FP-2 (IC(50)=2.7-13.2µM) and DHFR (IC(50)=1.8-19.8µM), and the inhibitory capability of compound 2o against FP-2 and DHFR were increased ∼8 and ∼6 times than that of compound 1, respectively. Moreover, compound 2o exhibited moderate in vivo antimalarial activity in a dose dependent fashion, its safety and survival rate were slightly better than that of positive drug. The preliminary SAR was obtained, meanwhile, molecular modeling result provided the key structural information to maintain the dual inhibitory activity, and was helpful for future dual inhibitors design.

Microwave-assisted one-pot synthesis of pyrazolone derivatives under solvent-free conditions.

An efficient one-pot method to generate structurally diverse and medicinally interesting pyrazolone derivatives in good to excellent yields of 51-98% under microwave irradiation and solvent-free conditions has been developed.

2-(3,4-dihydro-4-oxothieno[2,3-d]pyrimidin-2-ylthio) acetamides as a new class of falcipain-2 inhibitors. 3. design, synthesis and biological evaluation.

The cysteine protease falcipain-2 (FP-2) of Plasmodium falciparum is a principal cysteine protease and an essential hemoglobinase of erythrocytic P. falciparum trophozoites, making it become an attractive target enzyme for developing anti-malarial drugs. In this study, a series of novel small molecule FP-2 inhibitors have been designed and synthesized based on compound 1, which was identified by using structure-based virtual screening in conjunction with an enzyme inhibition assay. All compounds showed high inhibitory effect against FP-2 with IC(50)s of 1.46-11.38 microM, and the inhibitory activity of compound 2a was ~2 times greater than that of prototype compound 1. The preliminary SARs are summarized and should be helpful for future inhibitor design, and the novel scaffold presented here, with its potent inhibitory activity against FP-2, also has potential application in discovery of new anti-malarial drugs.