Development of fluorine-substituted NH2-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors: Boosting the safety and metabolic stability

Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1 (EC50 = 1.0 nmol/L), but the poor metabolic stability in human liver microsomes (t 1/2 = 14.6 min) and insufficient selectivity (SI = 2059) with high cytotoxicity (CC50 = 2.08 μmol/L) remained major issues associated with JK-4b. The present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b, leading to the discovery of a novel series of fluorine-substituted NH2-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain (EC50 = 1.8-349 nmol/L). The best compound 5t in this collection (EC50 = 1.8 nmol/L, CC50 = 117 μmol/L) was 32-fold in selectivity (SI = 66,443) compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains, such as L100I, K103N, E138K, and Y181C. The metabolic stability of 5t was also significantly improved (t 1/2 = 74.52 min), approximately 5-fold higher than JK-4b in human liver microsomes (t 1/2 = 14.6 min). Also, 5t possessed good stability in both human and monkey plasma. No significant in vitro inhibition effect toward CYP enzyme and hERG was observed. The single-dose acute toxicity test did not induce mice death or obvious pathological damage. These findings pave the way for further development of 5t as a drug candidate.

Novel compounds in Momordica charantia / 中草药

Objective To study new active constituents in the mature fruits of Momordica charantia.Methods M.charantia was extracted by alcohol and purified by D-101 macroporous adsorptive resin.The isolation and purification were carried out by silica gel and semiprepared HPLC,the compounds were identified and elucidated by spectral and chemical methods.Results Eight compounds were obtained and identified as charantadiol A(5?,19-epoxycucurbita-6,23(E),25(26)-triene-3?,19(R)-diol,Ⅰ),(+)-eduesmin(Ⅱ),bluemenol A(Ⅲ),karatavilagenin D(Ⅳ),5?,19-epoxycucurbita-6,23-diene-3?-19,25-triol(Ⅴ),5,19-epoxy-5?-cucurbita-6,23(E)-diene3?,25-diol(Ⅵ),3?,7?-trihydroxy-cucurbita-5,23(E)-diene-19-al(Ⅶ) and ?-sitosterol(Ⅷ).Conclusion Compound Ⅰ is a novel one,named charantadiol A.Compounds Ⅱ and Ⅲ are obtained from M.charantia for the first time.