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Conformational restriction design of thiophene-biphenyl-DAPY HIV-1 non-nucleoside reverse transcriptase inhibitors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2019 Nov 15; Vol. 182, pp. 111603. Date of Electronic Publication: 2019 Aug 08. - Publication Year :
- 2019
-
Abstract
- Conformational restriction is a promising strategy in the development of DAPY-type non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, eighteen thiophene-biphenyl-DAPY derivatives were designed and synthesized as potent HIV-1 NNRTIs in which halogen and methyl groups were introduced to explore the conformationally constrained effects. Molecular docking and dynamic simulation analysis indicated that substituents on different positions of the biphenyl ring induced different dihedral angles and binding conformations, further explaining their anti-viral activities. The 2'-fluoro and 3'-chloro substitutions could form electrostatic or halogen-bonding interactions with adjacent residues of the RT enzyme. The 2'-methyl group contributed to enlarge the dihedral angle of biphenyl ring and was positioned to a space-filling hydrophobic pocket. Notably, compounds 22 and 23 with two methyl groups exhibited potent biological activity against WT HIV-1-infected MT-4 cells (EC <subscript>50</subscript> = 14 and 17 nM, respectively) and RT enzyme (EC <subscript>50</subscript> = 27 and 42 nM, respectively). In particular, 23 exhibited much lower cytotoxicity (CC <subscript>50</subscript> = 264.19 μM) and higher selectivity index (SI = 18,564) than etravirine. Taken together, a rational conformational model for further design of DAPYs is proposed, providing a new guidance for the development of NNRTIs.<br /> (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Anti-HIV Agents chemical synthesis
Anti-HIV Agents chemistry
Biphenyl Compounds chemistry
Cell Line
Dose-Response Relationship, Drug
HIV Reverse Transcriptase metabolism
HIV-1 drug effects
Humans
Microbial Sensitivity Tests
Molecular Conformation
Pyrimidines chemistry
Reverse Transcriptase Inhibitors chemical synthesis
Reverse Transcriptase Inhibitors chemistry
Structure-Activity Relationship
Thiophenes chemistry
Anti-HIV Agents pharmacology
Biphenyl Compounds pharmacology
Drug Design
HIV Reverse Transcriptase antagonists & inhibitors
HIV-1 enzymology
Pyrimidines pharmacology
Reverse Transcriptase Inhibitors pharmacology
Thiophenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 182
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31421633
- Full Text :
- https://doi.org/10.1016/j.ejmech.2019.111603