Synthesis and biological evaluation of alkenyldiarylmethane HIV-1 non-nucleoside reverse transcriptase inhibitors that possess increased hydrolytic stability.
Non-nucleoside inhibitors of HIV reverse transcriptase (NNRTIs), albeit not the mainstays of HIV/AIDS treatment, have become increasingly important in highly active antiretroviral therapy (HAART) due to their unique mechanism of action. Several years ago our group identified the alkenyldiarylmethanes (ADAMs) as a potent and novel class of NNRTIs; however, the most active compounds were found to be metabolically unstable. Subsequent work has led to the synthesis of 33 analogues, with improved metabolic profiles, through the replacement of labile esters with various heterocycles, nitriles, and thioesters. As a result, a number of hydrolytically stable NNRTIs were identified with anti-HIV activity in the nanomolar concentration range. Furthermore, an improved pharmacophore model has been developed based on the new ADAM series, in which a salicylic acid-derived aryl ring is oriented cis to the side chain and the aryl ring that is trans to the side chain contains a hydrogen bond acceptor site within the plane of the ring.
Cullen
Matthew D
MD
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, Imquest Biosciences, 7340 Executive Way, Suite R, Frederick, Maryland 21704, USA.
Deng
Bo-Liang
BL
Hartman
Tracy L
TL
Watson
Karen M
KM
Buckheit
Robert W
RW
Pannecouque
Christophe
C
Clercq
Erik De
ED
Cushman
Mark
M
D000475:Alkenes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006868:Hydrolysis; D009154:Mutation; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D010080:Oxazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity