Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV-1 Activities and Improved Oral Bioavailability.

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives (6-26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher Cmax and AUC0-∞ and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 infection.

Design, synthesis and anti-HIV evaluation of 5-alkyl- 6-(benzo[d][1,3]dioxol-5-alkyl)-2-mercaptopyrimidin-4(3H)-ones as potent HIV-1 NNRTIs.

In order to discover and develop the new HIV-1 NNRTIs, a series of 5-alkyl-6-(benzo[d][1,3]dioxol-5-ylalkyl)-2-mercaptopyrimidin-4(3H)-ones was synthesized and screened for their in vitro cytotoxicity against HIV-1. Most of the compounds we synthetized showed high activity against wild-type HIV-1 strain (IIIB) while IC50 values are in the range of 0.06-12.95 µM. Among them, the most active HIV-1 inhibitor was compound 6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5b), which exhibited similar HIV-1 inhibitory potency (IC50 = 0.06 µM, CC50 = 96.23 µM) compared with nevirapine (IC50 = 0.04 µM, CC50 >200 µM) and most of compounds exhibited submicromolar IC50 values indicating they were specific RT inhibitors. The compounds 5b, 6-(benzo[d] [1,3]dioxol-5-yl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5c) and 4-(2-((4-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)acetyl)phenylbenzo[d][1,3]dioxole-5-carboxylate (5r) were selected for further study. It was found that all of them had little toxicity to peripheral blood mononuclear cell (PBMC), and had a good inhibitory effect on the replication of HIV-1 protease inhibitor resistant strains, fusion inhibitor resistant strains and nucleosides reverse transcriptase inhibitor resistant strains, as well as on clinical isolates. Besides, compound 5b and 5c showed inhibition of HIV-1 RT RNA-dependent DNA polymerization activity and DNA-dependent DNA polymerization activity, while compound 5r only showed inhibition of HIV DNA-dependent DNA polymerization activity, which was different from classical reverse transcriptase inhibitors. Our study which offered the preliminary structure-activity relationships and modeling studies of these new compounds has provided the valuable avenues for future molecular optimization.