Benzimidazole Ribonucleosides: Design, Synthesis, and Antiviral Activity of Certain 2-(Alkylthio)- and 2-(Benzylthio)-5,6-dichloro-1-(.beta.-D-ribofuranosyl)benzimidazoles

Abstract

Several 2-alkylthio- and 2-benzylthio derivatives of 5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (DRB) have been designed and synthesized from 5,6-dichloro-1-(beta-D-ribofuranosyl)-benzimidazole-2-thione. All compounds were evaluated for activity against human cytomegalovirus (HCMV) and/or herpes simplex virus type-1 (HSV-1). Three different cytotoxicity assays were used to determine if the compounds were toxic to uninfected cells. Most of the 2-alkylthio compounds were either inactive against HCMV and HSV-1 or were active only at concentrations at or near those which produced toxicity in uninfected cells. The best separation between activity against HCMV and cytotoxicity was observed with the 2-benzylthio analog 7. This prompted us to synthesize the substituted 2-benzylthio analogs 11-23 using a Topliss Tree approach. None of these compounds were more active than compound 7; most of the analogs were weakly active against both HCMV and HSV-1, but the activity was not separated from cytotoxicity. On the basis of both antiviral and cytotoxicity data, compound 7 was the best compound in the series. It was more active against HCMV than DRB (the 2-unsubstituted analog), acyclovir, and foscarnet, but it was less active than ganciclovir.

Experimental and QSAR Studies on Antimicrobial Activity of Benzimidazole Derivatives

“…This observed increase in activity is higher for compounds which have CH 2 OC 6 H 5 in their R position, when compared to those which have CH 2 C 6 H 5 in their R position. Figure 5 plots the effect of various electronegative functional groups in the R position (ϭCCl 3 pumilus and P. vulgaris respectively). More negative is the HOMO energy, lower is the activity.…”

“…Benzimidazoles fit this requirement well since they have demonstrated a diverse set of biological activities that include antibacterial, antiamoebic, antiviral, antifungal, [1][2][3][4] anthelmintic, 5) anti-HIV, 6) antihistaminic, [7][8][9] antiulcer, 10,11) cardiotonic, 12) antihypertensive 13,14) and neuroleptic. 15) They are also widely in clinical use.…”

Synthesis of Some Novel N-Substituted 2-(4-Bromo-Phenoxymethyl)-1h-Benzimidazole Derivatives and Their Antimicrobial Evaluation

“…Then the condensation of 4-bromophenoxy acetic acid (2) with o-phenylenediamine (1) gives 2-(4-bromo-phenoxymethyl)-1H-benzimidaziole (3). N-alkylation, acylation and sulphonation of condensed product get series of some novel N-substituted 2-(4-bromophenoxymethyl)-1H-benzimidazole derivatives.…”

“…The benzimidazole nucleus, which is a useful structure for research and development of new pharmaceutical molecules, Benzimidazoles are among the important heterocyclic compounds found in several natural and non-natural products such as vitamin B 12 1 , marine alkaloid kealiiquinone 2 , and benzimidazole nucleosides 3 etc. Some of the benzimidazole derivatives are marketed as anti-fungal 4 , anti-helmintic 5 and anti-psychotic 6 drugs and other derivatives have been found to possess some interesting bioactivities such as antitubercular 7 , anti-cancer 8 , HIV-Inhibitors 9 , Anti-Hypertensive Agent 10 , Anti-Inflammatory activity 11 , Anti-allergic activity 12 , Anti-diabetic Activity 13 , Anticonvulsant activity 14 and DNA Inhibitory Activity 15 etc.…”

Synthesis and Anti-Herpes Activity of a Series of Indolizines

“…3). The 3-(1-ribofuranosyl) compound 41 was synthesized as an analogue of the anti HCMV benzimidazole ribosides reported by Townsend's group (Devivar et al, 1994). The compound was easily prepared by application of the Vorbruggen (1981) methodology normally used in the synthesis of nucleosides (Fig.…”