Arylazolyl(azinyl)thioacetanilides. Part 10: Design, synthesis and biological evaluation of novel substituted imidazopyridinylthioacetanilides as potent HIV-1 inhibitors

By means of scaffold hopping strategy, imidazopyridine was used as a new bioisostere to replace the five-membered heterocyclic lead structures. This strategy led to the identification of imidazopyridinylthioacetanilide NNRTIs with potency against HIV-1 replication in the low micromolar concentration...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2012-09, Vol.20 (18), p.5527-5536
Main Authors: Li, Xiao, Zhan, Peng, Liu, Hong, Li, Dongyue, Wang, Liu, Chen, Xuwang, Liu, Huiqing, Pannecouque, Christophe, Balzarini, Jan, Clercq, Erik De, Liu, Xinyong
Format: Article
Language:English
Subjects:
Acetanilides - chemical synthesis
Acetanilides - chemistry
Acetanilides - pharmacology
Anti-HIV Agents - chemical synthesis
Anti-HIV Agents - chemistry
Anti-HIV Agents - pharmacology
Anti-HIV-1 activity
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
bioactive properties
Biological and medical sciences
Cell Line
Dose-Response Relationship, Drug
Drug Design
Heterocycle
HIV
HIV-1 - drug effects
HIV-1 - physiology
Human immunodeficiency virus 1
Humans
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
Imidazopyridine
Indexing in process
Medical sciences
Microbial Sensitivity Tests
Molecular Structure
NNRTIs
pharmacology
Pharmacology. Drug treatments
SAR
Scaffold hopping
Structure-Activity Relationship
structure-activity relationships
Synthesis
Virus Replication - drug effects
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Summary:By means of scaffold hopping strategy, imidazopyridine was used as a new bioisostere to replace the five-membered heterocyclic lead structures. This strategy led to the identification of imidazopyridinylthioacetanilide NNRTIs with potency against HIV-1 replication in the low micromolar concentration range. [Display omitted] In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with novel structures, we have employed a scaffold hopping strategy to explore the chemically diversed space of bioactive compounds. The original arylazolylthioacetanilide platform was replaced with different imidazopyridinyl- thioacetanilide scaffolds to yield the optimal pharmacophore moieties in order to generate novel NNRTIs with desirable potency. Some of the new compounds proved able to inhibit HIV-1 replication in the low micromolar range. In particular, compound 5b16 displayed the most potent anti-HIV-1 activity (EC50=0.21±0.06μM), inhibiting HIV-1 IIIB replication in MT-4 cells more effectively than dideoxycytidine (EC50=1.4±0.1μM) and similarly with nevirapine (EC50=0.20±0.10μM). Preliminary structure–activity relationship (SAR) of the newly synthesized congeners is discussed, and molecular modeling study is performed to rationalize the SAR conclusions.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2012.07.026