Design, synthesis and biological evaluation of 3-substituted 2,5-dimethyl-N-(3-(1H-tetrazol-5-yl)phenyl)pyrroles as novel potential HIV-1 gp41 inhibitors.
Based on the structure of HIV-1 gp41 binding site for small-molecule inhibitors, optimization of lead 2 resulted in the discovery of a new series of 2,5-dimethyl-3-(5-(N-phenylrhodaninyl)methylene)-N-(3-(1H-tetrazol-5-yl)phenyl)pyrrole compounds with improved anti-HIV-1 activity. The most active compounds 13a and 13j exhibited significant potency against gp41 6-HB formation with IC(50) values of 4.4 and 4.6 μM and against HIV-1 replication in the MT-2 cells with EC(50) values of 3.2 and 2.2 μM, respectively, thus providing a new starting point to develop highly potent small-molecule HIV fusion inhibitors targeting gp41.
Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Xiao-Yang
XY
He
Peng
P
Zou
Jiayin
J
Qiu
Ling
L
Hou
Shibo
S
Jiang
Shuwen
S
Liu
Lan
L
Xie
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000494:pharmacology
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D011758:Pyrroles; D013777:Tetrazoles; C045574:1H-tetrazole