A series of 22 benzimidazoles, having several substituents on the azole and benzene nuclei, were prepared and evaluated in vitro for antimicrobial activity. At first 2-chloro or 2-chloromethyl-5(6>sbsti~ed-lH-benzimidazoles were synthesized, which were then substituted at C-2 with several piperazine or piperidine derivatives. The antibadend activity of these compounds against Staphylococcus aureus, Bacillus subtilis, Eschenchia coli, and Pseudomotm aeruginom, and the antifungal activity against Candih albicans. Cadida stellatoidea, C d h p r a p s i l o s i s , and Candidapseudotropicalis were determined as the MIC values. Since compound 12 exhibits good activity, in order to clarify the effea of substituents at C-1 on the activity, benzimidazole derivatives having ethyl, allyl, benzyl. andp-fluorobenzyl substituents at C-1 were prepared, and slightly increased activity was seen.
Synthese und antimikmbielle
Aktivitiit 1,2,5(6)-trisubstiterter Benzimidazole 22 Benzimidazole mit verschiedenen Substituenten am Azolund Benzd-Ring wurden synthetisiert und in vitm auf antimibobielle W i r h g gepriift.-Zuerst wurden 2-Chloroder 2-Chlonnethyl-5(6>substituie~ 1H-benzimidazole hergestellt, die nit unterschiedlichen Piperazin-bzw. Pipendin-Derivaten an C-2 substituiert wurden. Die antibakterielle Aktivitit (MIC-Werte) dieser Verbindungen wurde gegen Stqhylococcus aureus, Bacillus subtilis, Eschenchia coli, Pseudomonas aeruginosa, die antimykotische Wirksamkeit gegen Candida albicans, Cami5h skhtok&m, Gmdiah pampsilosis und Candihpseudotropicalis bestimt. Da Verbindung 12 gut wirkt, wurden Benzimidazol-Derivate mit Substituenten an C-1 (Ethyl, Allyl, Benzyl und pFluorbenzyl) hergestellt. um den EinfluB der C-1-Substitution auf die Wirbamkeit zu untersuchen: Diese Substitution verstirkt die Wirhng ein wenig.
Recently, the antimicrobial effect of benzimidazoles has been studied extensively. Particularly substituted 2-aminobenzimidazole derivatives have received much attention la). In addition, carbamate derivatives of the 2-aminobenzimidazoles have been synthesized for their significant in vivo antifilarial activitylb). A series of 1 6 substituted 2-(2-hydroxyphenyl)benzimidazoles were prepared as potential agents for the control of periodontitis against Actinomycetes viscosus and Bactenodes gingivalis2'. Pyrimido[l,&a]benzimidazoles have been developed as a new class of inhibitors of DNA gyrase and their synthesis and potent antibacterial activities were reported3). Jung et al4)have synthesized new cephalosporin derivatives which possess an aminobenzimidazole ring at C-7; these cephalosporins have a broad spectrum of antibacterial activit . The influence of the substituents at C-l? C-21a"'s11), and C-5(6)3*6*10.'y' on the antimicrobial activity of the benzimidazole ring are well known. On the other side, various heterocycles linked to benzimidazole exhibit some potent antimicrobial activity 3.12-15) In this study, we report on synthesis, antibacterial, and antifungal activities of new benzimidazoles which were linked with piperazine or piperidine moieties, along with a study of their isomeric character. Chemistry methyl benzimidazole precursors of 1-14 were prepared b (Scheme 1).
Treatment of these 2-chloromethylbenzimidazoles with several piperazine and piperidine derivatives afforded compounds 1-6 and 7-14, respectively.
1-Substituted 2-(4-methylpiperidin-1-yl) methylbenzimidazoles 12a-126 were prepared by alkylation of 12 (Scheme 2). Because of the non-symmetrical benzimidazole ring and of its tautomeric character, two regioisomers (5-chloro and The 5(6)-[chloro, nitro, methyl or hydrogen], 2-chlorothe methods of Knobloch16), Sieganl7) and Tatsuoka 14 1 -C 7 -12.13.14 Scheme 1 K2 121l l d Scheme 2 6-chloro derivatives) have occurred with the approximately same ratio. Regioselective synthesis for 1% was accomplished according to Scheme 3. Reduction of 17 with Zn/HCl produced 18 which was cyclized to 19 upon heating in the 4N HCl. The reaction of 19 with 4-methylpiperidine gave 12e, as an isomer of 126.