Design, synthesis, and SAR of naphthyl-substituted Diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase.
A series of 38 2-naphthyl-substituted diarylpyrimidine (DAPY) analogues, characterized by various substitution patterns on the pyrimidine and naphthalene rings, was synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of the HIV-1 wild-type and double mutant (K103N+Y181C) strains. Most of the compounds displayed strong activity against wild-type HIV-1. The most active compound, with a cyano group at position C6 on the naphthalene ring, exhibited activity against wild-type HIV-1 with an EC50 value of 0.002 microM and against the double mutant strain with an EC50 value of 0.24 microM; the selectivity index (SI) against wild-type is >180 000, the highest SI value among DAPY analogues. The structure-activity relationship (SAR) of the newly synthesized DAPYs is presented herein.
Liang
Yong-Hong
YH
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Feng
Xiao-Qing
XQ
Zeng
Zhao-Sen
ZS
Chen
Fen-Er
FE
Balzarini
Jan
J
Pannecouque
Christophe
C
De Clercq
Erik
E
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase