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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.
- Source :
-
Bioorganic Chemistry . Sep2020, Vol. 102, pN.PAG-N.PAG. 1p. - Publication Year :
- 2020
-
Abstract
- • A novel series of S -DABO derivatives have been designed and synthesized. • Selected compounds displayed potent activity against different HIV-1 strains. • Compound 5r only showed inhibition of HIV-1 DPDP activity unlike classical NNRTIs. • Preliminary SAR and molecular modeling of these novel congeners were investigated. 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 IC 50 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 (IC 50 = 0.06 μM, CC 50 = 96.23 μM) compared with nevirapine (IC 50 = 0.04 μM, CC 50 >200 μM) and most of compounds exhibited submicromolar IC 50 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00452068
- Volume :
- 102
- Database :
- Academic Search Index
- Journal :
- Bioorganic Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 145443322
- Full Text :
- https://doi.org/10.1016/j.bioorg.2020.104041