Synthesis, biological activity, and crystal structure of potent nonnucleoside inhibitors of HIV-1 reverse transcriptase that retain activity against mutant forms of the enzyme.
In an ongoing effort to develop novel and potent nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors that are effective against the wild type (WT) virus and clinically observed mutants, 1,2-bis-substituted benzimidazoles were synthesized and tested. Optimization of the N1 and C2 positions of benzimidazole led to the development of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (1) (IC50 = 0.2 microM, EC50 = 0.44 microM, and TC50 >/= 100 against WT). This paper describes how substitution on the benzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhanced potency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A 7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT provided the basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivatives were nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants.
Molecular Aspects of Drug Design Section and Retroviral Replication Laboratory, National Cancer Institute-Frederick, P.O. Box B, Frederick, Maryland 21702, USA.
Marshall L
ML
Morningstar
Thomas
T
Roth
David W
DW
Farnsworth
Marilyn Kroeger
MK
Smith
Karen
K
Watson
Robert W
RW
Buckheit
Kalyan
K
Das
Wanyi
W
Zhang
Eddy
E
Arnold
John G
JG
Julias
Stephen H
SH
Hughes
Christopher J
CJ
Michejda
D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase