Original article Synthetic studies on novel benzimidazolopeptides with antimicrobial, cytotoxic and anthelmintic potential Rajiv Dahiya * , Devender Pathak Department of Pharmaceutical Chemistry, Rajiv Academy for Pharmacy, NH#2, DelhieMathura Bypass Road, PO Chattikara, Mathura 281 001, Uttar Pradesh, India Received 22 May 2006; received in revised form 30 November 2006; accepted 30 November 2006 Available online 15 December 2006 Abstract Four substituted benzimidazolyl-benzoic/salicylic acids 5e8 were synthesized by interaction of 5,6-dimethyl-/6-nitrobenzimidazoles with diazotized substituted/unsubstituted aminobenzoic acids in the presence of cupric chloride. The coupling of compounds 5e8 with different amino acid ester hydrochlorides/dipeptide/tripeptide/tetrapeptide methyl esters afforded novel benzimidazolopeptide derivatives 5aef, 6aeh, 7aeg and 8aeg. The structures of all newly synthesized compounds were established on the basis of analytical, IR, 1 H NMR, 13 C NMR and mass spectral data. Selected peptide ester derivatives were further hydrolyzed by using lithium hydroxide (LiOH) to yield corresponding acid derivatives 5b a ed a , 6e a eg a , 7c a ee a and 8e a eg a . All peptide derivatives were screened for their antimicrobial, anthelmintic and cytotoxic activities. Almost all newly synthesized benzimidazolopeptides have shown moderate to good anthelmintic activity against all three earthworm species and good antimicrobial activity against pathogenic fungal strains Candida albicans and Aspergillus niger, gram negative bacterial strains Pseudomonas aeruginosa and Escherichia coli. Compounds 8g and 8g a possessed significant cytotoxic activity against Dalton’s lymphoma ascites (DLA) and Ehrlich’s ascites carcinoma (EAC) cell lines. Ó 2006 Elsevier Masson SAS. All rights reserved. Keywords: Benzimidazoles; 5-Aminosalicylic acid; p-Aminobenzoic acid; Peptides; Antimicrobial activity; Anthelmintic activity; Cytotoxicity 1. Introduction In past decades, benzimidazole and its derivatives have received much attention due to their chemotherapeutic value in the development of novel anthelmintics and antimicrobial agents [1e3]. Benzimidazole analogs also possessed other pharmacological activities such as antiallergic [4], antimyco- bacterial [5], inhibitory activity of human blood platelet aggre- gation [6], antiviral [7], antiprotozoal and antimalarial [8], anti-inflammatory, analgesic and kinase, DHFR inhibitory activity [9,10], antitumoral and tracheal relaxant activity [11]. Moreover, the literature is enriched with several reports indicating antimicrobial and molluscicidal [12], cytotoxicity [13], prooxidant and antioxidant [14], anti-inflammatory and analgesic [15] potential of substituted benzoic acid analogs, in addition to inhibitory activity against aldose reductase, influenza neuraminidase, 3a-hydroxysteroid dehydrogenase, phosphodiesterase (4D), steroid 5a-reductase isozymes 1 and 2, homomeric kainate receptor, histamine H 1 receptor and estrone sulfatase [16e23]. Prompted from the chemotherapeutic importance of benz- imidazoles and benzoic acid derivatives, these two vital moie- ties were combined together into single nucleus by varying the substitution pattern on both the moieties to yield 4-(5,6-di- methyl-1H-benzo[d]imidazol-2-yl)-benzoic acid 5 and 4-(5, 6-dimethyl-1H-benzo[d]imidazol-2-yl)-3,5-diiodobenzoic acid 6, 2-hydroxy-5-(6-nitro-1H-benzo[d]imidazol-2-yl)-benzoic acid 7 and 5-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-2-hy- droxybenzoic acid 8. * Corresponding author. Tel.: þ91 565 6531680, +91 9897417450 (mobile). E-mail addresses: rajivdahiya77@rediffmail.com, rajivdahiya04@yahoo. co.in (R. Dahiya). 0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2006.11.015 European Journal of Medicinal Chemistry 42 (2007) 772e798 http://www.elsevier.com/locate/ejmech