Australian Journal of Basic and Applied Sciences, 1(4): 525-532, 2007 ISSN 1991-8178 Corresponding Author: Rajiv Dahiya, Assistant Professor, Department of Pharmaceutical Chemistry, Rajiv Academy for Pharmacy, NH#2, Delhi-Mathura Bypass Road, PO Chattikara, Mathura-281 001, Uttar Pradesh (UP), India. Tel: 09897417450, 0565 6531680. E-mail: rajivdahiya04@yahoo.co.in, rajivdahiya77@rediffmail.com 525 Synthesis and Biological Screening of a Novel Series of 3,4,5-Trisubstituted Phenoxyacetic Acid Analogs Rajiv Dahiya and Ramninder Kaur Department of Pharmaceutical Chemistry, Rajiv Academy for Pharmacy, Mathura-281 001 (UP), India. Abstract: Present investigation describes the synthesis of a novel series of 3,4,5-trisubstitutedphenoxy acetyl amino acids and peptides by coupling the 2-(4-chloro-3,5-dimethylphenoxy)acetic acid with different amino acid methyl ester hydrochlorides/peptide methyl esters using dicyclohexylcarbodiimide (DCC) as the coupling agent and N-methylmorpholine (NMM) as the base. The structures of peptide derivatives were elucidated by elemental analysis as well as FTIR, H NMR, C NMR and mass 1 13 spectral data. The newly synthesized compounds were also evaluated for their antibacterial, antifungal and anthelmintic potential. Compounds 6, 10 and 12 were found to possess potent anthelmintic activity against M. konkanensis, P. corethruses and Eudrilus sp. and compound 13 displayed better activity against pathogenic fungus C. albicans, in addition to potent antibacterial activity exhibited by compounds 8 and 10 against gram negative bacteria P. aeruginosa. Keywords: phenoxy acetic acid; amino acids; peptides; antimicrobial activity; anthelmintic activity INTRODUCTION Phenoxyacetic acid is among the most vital moieties which are associated with potent fungicidal activities. Aryloxyacetic acid derivatives possess a wide array of diverse bioactivities including antimycobacterial (Ali and Shaharyar, 2007; Shaharyar et al., 2006), anti-inflammatory and antioxidant (Kunsch et al., 2005), antibacterial (Iqbal et al., 2007), analgesic (Sato et al., 2002), antisickling (Abraham et al., 1989), antilipaemic 2 and antiplatelet (Perez-Pasten et al., 2006; Metz and Specker, 1980), nonprostanoid prostacyclin (PGI ) mimetics (Meanwell et al., 1993), gastrin/cholecystokinin (CCK)-B receptor antagonistic activity (Takeda et al ., 1998), inhibitory activity of cathepsin K and aldose reductase (Shinozuka et al., 2006; Van Zandt et al., 2004), diuretic (Kitagawa et al., 1991; Bicking et al., 1976) and growth regulators (Osborne et al., 1955). Further, the review of literature has suggested that incorporation of amino acids and peptides into the aromatic and heterocyclic congeners have resulted in analogs exhibiting potent pharmacological activities (Poojary et al., 2003; Himaja et al., 2003). Thus keeping in view the biological potency of phenoxy acetic acids as well as taking advantage of biodegradability and biocompatibility of peptides and further, in continuation of our work on synthesizing potent heterocyclic and other aromatic analogs of amino acids/peptides (Dahiya and Pathak, 2007; Dahiya et al., 2006; Dahiya and Pathak 2006; Dahiya and Pathak 2006a), a novel series of 2-(4- chloro-3,5-dimethylphenoxy)acetic acid derivatives of amino acids and peptides was synthesized with an anticipation to get novel compounds with more therapeutic efficacy and fewer side effects. 2-(4-Chloro-3,5-dimethylphenoxy)acetic acid 1 was prepared by phenoxylation of 4-chloro-3,5- dimethylphenol with monochloroacetic acid in presence of alkali. Dipeptides Boc-L-Pro-L-Phe-OMe, Boc-Gly- Gly-OMe, Boc-L-His-L-Leu-OMe were prepared by coupling of Boc-protected amino acids viz. Boc-L-Pro-OH, Boc-Gly-OH and Boc-L-His-OH with respective amino acid methyl ester hydrochlorides such as L-Phe- OMe.HCl, Gly-OMe.HCl and L-Leu-OMe.HCl using DCC and triethylamine (TEA) as the base. Similarly, tripeptides Boc-L-Try-L-nitro(Arg)-L-Try-OMe and Boc-L-Pro-L-Pro-L-Pro-OMe were prepared by coupling dipeptide methyl esters L-nitro(Arg)-L-Try-OMe and L-Pro-L-Pro-OMe with Boc-L-Try-OH and Boc-L-Pro-OH respectively. Compound 1 was coupled with amino acid methyl ester hydrochlorides L-Tyr-OMe.HCl, L-Ile-OMe.HCl, L-Val-OMe.HCl, L-Try-OMe.HCl and deprotected di/tripeptides using DCC and NMM to yield novel 2-(4- chloro-3,5-dimethylphenoxy)acetyl amino acids/peptide methyl esters (2-10). Selected ester derivatives 2, 6 and 9 were further hydrolyzed using lithium hydroxide to get respective free acids 11-13 (Fig. 1).