Synthesis, Biological Activity, and Crystal Structure of Potent Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase That Retain Activity against Mutant Forms of the Enzyme

Abstract

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.

Human Immunodeficiency Virus Reverse Transcriptase: 25 Years of Research, Drug Discovery, and Promise

“…In contrast, NNRTIs, e.g. NVP and efavirenz, impose allosteric control of DNA synthesis by occupying a site at the base of the p66 thumb that "locks" this subdomain in a config-uration incompatible with catalysis (19,70). Subsequent SMS analysis indicated an additional property of NNRTIs of inducing dislocation of HIV-1 RT from the polymerization target site and sliding on the nucleic acid duplex.…”

Synthesis and evaluation of novel $N,N'$-disubstituted benzimidazolium bromides salts as antitumor agents

“…Many benzimidazole derivatives possess a variety of biological properties such as antiulcer, 5 antihypertensive, 6 antiviral, 7 antihelmentic, 8 antifungal, 9 antibacterial, 10 and antitubercular agents, 11 and several other kinds of therapeutic agent that are still under investigation for their antitumor properties. 5−18 In the literature, various benzimidazole derivatives showed remarkable and promising antitumor properties.…”

Chemoselective Synthesis of 2-Aryl-1-arylmethyl-1H-benzo[d]imidazoles Using Indion 190 Resin as a Heterogeneous Recyclable Catalyst

“…A number of improved methods have been developed for the synthesis of benzimidazoles involves a reaction between an o-phenylendiamine and a carboxylic acid or its derivative (nitrile, amidate and orthoester) under harsh dehydrating condition. [14][15][16][17] The most popular strategies for the synthesis of 1,2-disubstitted benimidazoles include N-alkylation of 2-substituted benimidazole in the presence of strong base, 18,19 N-alkylation of o-nitroanilides followed by a reductive cyclization, 20,21 cyclocondensation of N-substituted o-aminoanilides, 22 and the condensation of N-substituted phenylenediamine with sodium salt of α-hydroxy benzylsulphonic acid. 23 In addtion, 1,2-disbstituted benzimidazoles are also be accessed by direct one-step condensation of o-phenylenediamines with aldehydes by involving the influence of different acid catalysts under various reaction conditions [24][25][26][27][28][29][30][31][32][33] or by using polymer-supported hypervalent iodine (PDIAS) as a reagent.…”