Benzimidazole condensed ring systems. 1. Syntheses and biological investigations of some substituted pyrido[1,2‐a]benzimidazoles

Abstract

The synthesis of some substituted 3‐hydroxy‐1‐oxo‐1H,5H‐pyrido[1,2‐a]benzimidazole‐4‐carbonitriles and 4‐ethyl carboxylates 3 and their 0‐ and N‐dialkyl derivatives 5,6 is described. 3‐Ethoxy‐5‐ethyl‐2‐phenyl‐1H,5H‐pyrido[1,2‐a]benzimidazol‐1‐one 7 was obtained during the course of ethylating the parent ester 3t with triethyl phosphate. Chlorination of 3 with phosphorus oxychloride afforded the corresponding 1,3‐dichloropyrido[1,2‐a]benzimidazoles 8 which were converted to a variety of azido, amino, morpholino and methoxy derivatives of the system. The synthesis of the indolopyridobenzimidazole 15 is also described. Two compounds exhibited in vitro antibacterial activity. Many compounds were screened for antileukemic, antimicrobial, herbicidal and plant antifungal potencies but were inactive.

Malonates in Cyclocondensation Reactions

“…2-Cyanomethylbenzimidazole 22 was used as 1,3-dinucleophilic substrate for cyclocondensation with bis(trimethylsilyl) malonates 19 . According to a previous investigation [15] the dinucleophile 22 reacts readily with reactive bis(2,4,6-trichlorophenyl) malonates 18 in refluxing bromobenzene at 150°C to give pyrido[1,2- a ]benzimidazoles. The reaction of bis(trimethylsilyl) malonates 19 in refluxing bromobenzene, however, gave only C-acylation to yield 2-(2,3-dihydro-1 H -benzimidazol-2-yliden)-3-oxoalkane-nitriles 23 without cyclization to the nitrogen (Scheme 8).…”

Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model

“…The benzimidazole motif is a recognized privileged scaffold in medicinal chemistry due to its capacity to interact with numerous biological systems, leading to a wide variety of biological activities, including antimalarial activity. − Pyrido­[1,2- a ]­benzimidazoles (PBIs), previously investigated for antibacterial, antifungal, antiviral, and antitumor activities, were recently shown to be a novel antimalarial chemotype . The lead compound from the previous studies, 8 (Figure ), showed high antiplasmodial activity in vitro (IC 50 ( Pf NF54) = 0.11 μM; IC 50 ( Pf K1) = 0.12 μM) and promising oral efficacy (96% at 4 × 50 mg/kg p.o.)…”

N,N-Dialkyl-N′-Chlorosulfonyl Chloroformamidines in Heterocyclic Synthesis. Part XIV. Synthesis and Reactivity of the New Benzo[4,5]imidazo[1,2-b][1,2,6]thiadiazine Ring System

“…After cooling, the precipitate was collected, washed with water and with CH 2 Cl 2 (3 × 10 mL) to give the title S2 compound 4d (184 mg, 70%) as a tan solid; mp 202-203 °C (lit [9] Ethyl 2-(1H-benzo[d]imidazol-2-yl)acetate 8 [8] Prepared by a literature procedure. [11] Thus, acetyl chloride (1 mL, 14 mmol) was added dropwise to a stirred solution of benzimidazole acetonitrile 4a (500 mg, 3.18 mmol) in EtOH (8 mL) at 0 °C. The reaction mixture was heated at reflux for 2 h, cooled to room temperature and the remaining solvent removed in vacuo.…”