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Discovery of Novel Dihydrothiopyrano[4,3- d ]pyrimidine Derivatives as Potent HIV-1 NNRTIs with Significantly Reduced hERG Inhibitory Activity and Improved Resistance Profiles.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Sep 23; Vol. 64 (18), pp. 13658-13675. Date of Electronic Publication: 2021 Aug 25. - Publication Year :
- 2021
-
Abstract
- Enlightened by the available structural biology information, a novel series of dihydrothiopyrano[4,3- d ]pyrimidine derivatives were rationally designed via scaffold hopping and molecular hybridization strategies. Notably, compound 20a yielded exceptionally potent antiviral activities (EC <subscript>50</subscript> = 4.44-54.5 nM) against various HIV-1 strains and improved resistance profiles (RF = 0.5-5.6) compared to etravirine and rilpivirine. Meanwhile, 20a exhibited reduced cytotoxicity (CC <subscript>50</subscript> = 284 μM) and higher SI values (SI = 5210-63992). Molecular dynamics simulations were performed to rationalize the distinct resistance profiles. Besides, 20a displayed better solubility (sol. = 12.8 μg/mL) and no significant inhibition of the main CYP enzymes. Furthermore, 20a was characterized for prominent metabolic stability and in vivo safety properties. Most importantly, the hERG inhibition profile of 20a (IC <subscript>50</subscript> = 19.84 μM) was a remarkable improvement. Overall, 20a possesses huge potential to serve as a promising drug candidate due to its excellent potency, low toxicity, and favorable drug-like properties.
- Subjects :
- Animals
Anti-HIV Agents chemical synthesis
Anti-HIV Agents metabolism
Anti-HIV Agents toxicity
Cell Line
HIV Reverse Transcriptase chemistry
HIV Reverse Transcriptase metabolism
HIV-1 drug effects
HIV-1 enzymology
Humans
Mice
Microbial Sensitivity Tests
Microsomes, Liver metabolism
Molecular Dynamics Simulation
Molecular Structure
Protein Binding
Pyrans chemical synthesis
Pyrans metabolism
Pyrans toxicity
Pyrimidines chemical synthesis
Pyrimidines metabolism
Pyrimidines toxicity
Rats, Sprague-Dawley
Reverse Transcriptase Inhibitors chemical synthesis
Reverse Transcriptase Inhibitors metabolism
Reverse Transcriptase Inhibitors toxicity
Structure-Activity Relationship
Rats
Anti-HIV Agents pharmacology
Pyrans pharmacology
Pyrimidines pharmacology
Reverse Transcriptase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34432448
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c01015