Diarylaniline derivatives as a distinct class of HIV-1 non-nucleoside reverse transcriptase inhibitors.
By using structure-based drug design and isosteric replacement, diarylaniline and 1,5-diarylbenzene-1,2-diamine derivatives were synthesized and evaluated against wild type HIV-1 and drug-resistant viral strains, resulting in the discovery of diarylaniline derivatives as a distinct class of next-generation HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) agents. The most promising compound 37 showed significant EC(50) values of 0.003-0.032 microM against HIV-1 wild-type strains and of 0.005-0.604 microM against several drug-resistant strains. Current results also revealed important structure-activity relationship (SAR) conclusions for diarylanilines and strongly support our hypothesis that an NH(2) group on the central benzene ring ortho to the aniline moiety is crucial for interaction with K101 of the NNRTI binding site in HIV-1 RT, likely by forming H-bonds with K101. Furthermore, molecular modeling studies with molecular mechanism/general Born surface area (MM/GBSA) technology demonstrated the rationality of our hypothesis.
Qin
Bingjie
B
Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
Jiang
Xingkai
X
Lu
Hong
H
Tian
Xingtao
X
Barbault
Florent
F
Huang
Li
L
Qian
Keduo
K
Chen
Chin-Ho
CH
Huang
Rong
R
Jiang
Shibo
S
Lee
Kuo-Hsiung
KH
Xie
Lan
L
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D000814:Aniline Compounds; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase