Back to Search
Start Over
Design, synthesis, and antiviral evaluation of novel hydrazone-substituted thiophene[3,2-d]pyrimidine derivatives as potent human immunodeficiency virus-1 inhibitors.
- Source :
-
Chemical biology & drug design [Chem Biol Drug Des] 2018 Dec; Vol. 92 (6), pp. 2009-2021. Date of Electronic Publication: 2018 Aug 26. - Publication Year :
- 2018
-
Abstract
- In the previous studies of our laboratory, the thiophene[3,2-d]pyrimidine was identified as a promising scaffold for seeking highly potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). In this study, we designed, synthesized, and biologically evaluated a series of thiophene[3,2-d]pyrimidine derivatives with changed linker between the thiophenepyrimidine core and the right wing. Some of the synthesized compounds exhibited excellent HIV-1 inhibitory potency with low (double-digit) nanomolar 50% effective concentration (EC <subscript>50</subscript> ) values. Among them, compound 13a exhibited the most potent anti-HIV-1 activity (EC <subscript>50</subscript>  = 21.2 nM), which was 10-fold greater than that of NVP (EC <subscript>50</subscript>  = 281 nM). Moreover, 13a showed much lower cytotoxicity (CC <subscript>50</subscript>  = 183 μM) and higher selection index (SI = 8,632) than NVP, ETV, and AZT. Besides, some physicochemical properties and water solubility were calculated or measured. The preliminary structure-activity relationships and molecular simulation studies of these compounds were also discussed comprehensively to provide valuable direction for further design and optimization.<br /> (© 2018 John Wiley & Sons A/S.)
- Subjects :
- Binding Sites
Genotype
HIV Reverse Transcriptase antagonists & inhibitors
HIV Reverse Transcriptase genetics
HIV Reverse Transcriptase metabolism
HIV-1 enzymology
HIV-1 genetics
Humans
Molecular Dynamics Simulation
Protein Structure, Tertiary
Pyrimidines chemical synthesis
Pyrimidines chemistry
Reverse Transcriptase Inhibitors chemistry
Reverse Transcriptase Inhibitors pharmacology
Solubility
Structure-Activity Relationship
Thiophenes chemistry
Drug Design
HIV-1 drug effects
Hydrazones chemistry
Pyrimidines pharmacology
Reverse Transcriptase Inhibitors chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1747-0285
- Volume :
- 92
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Chemical biology & drug design
- Publication Type :
- Academic Journal
- Accession number :
- 30079476
- Full Text :
- https://doi.org/10.1111/cbdd.13373