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Identification of novel potent HIV-1 inhibitors by exploiting the tolerant regions of the NNRTIs binding pocket.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 Mar 15; Vol. 214, pp. 113204. Date of Electronic Publication: 2021 Jan 24. - Publication Year :
- 2021
-
Abstract
- With our previously identified potent NNRTIs 25a and HBS-11c as leads, series of novel thiophene[3,2-d]pyrimidine and thiophene[2,3-d]pyrimidine derivatives were designed via molecular hybridization strategy. All the target compounds were evaluated for their anti-HIV-1 activity and cytotoxicity in MT-4 cells. Compounds 16a1 and 16b1 turned out to be the most potent inhibitors against WT and mutant HIV-1 strains (L100I, K103N, and E138K), with EC <subscript>50</subscript> values ranging from 0.007 μM to 0.043 μM. Gratifyingly, 16b1 exhibited significantly reduced cytotoxicity (CC <subscript>50</subscript>  > 217.5 μM) and improved water solubility (S = 49.3 μg/mL at pH 7.0) compared to the lead 25a (S < 1 μg/mL at pH 7.0, CC <subscript>50</subscript>  = 2.30 μM). Moreover, molecular docking was also conducted to rationalize the structure-activity relationships of these novel derivatives and to understand their key interactions with the binding pocket.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Anti-HIV Agents chemical synthesis
Anti-HIV Agents chemistry
Cell Line, Tumor
Cell Survival drug effects
Dose-Response Relationship, Drug
HIV Reverse Transcriptase metabolism
Humans
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Pyrimidines chemical synthesis
Pyrimidines chemistry
Reverse Transcriptase Inhibitors chemical synthesis
Reverse Transcriptase Inhibitors chemistry
Structure-Activity Relationship
Thiophenes chemical synthesis
Thiophenes chemistry
Anti-HIV Agents pharmacology
HIV Reverse Transcriptase antagonists & inhibitors
HIV-1 drug effects
Pyrimidines pharmacology
Reverse Transcriptase Inhibitors pharmacology
Thiophenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 214
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33567378
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113204