Synthesis, Characterization and Biological evaluation of 6-substituted-2-(substituted-phenyl)-quinoline derivatives bearing 4-amino-1,2,4-triazole-3-thiol ring at C-4 position

Available online at www.ilcpa.pl International Letters of Chemistry, Physics and Astronomy 8 (2014) 30-37 ISSN 2299-3843 Synthesis, Characterization and Biological evaluation of 6-substituted-2-(substituted-phenyl)quinoline derivatives bearing 4-amino-1,2,4-triazole3-thiol ring at C-4 position R. G. Vaghasiya*, H. B. Ghodasara, P. R. Vachharajani, V. H. Shah Department of Chemistry, Saurashtra University, University Road, Rajkot 360 005, Gujarat, India *E-mail address: ABSTRACT Quinoline derivatives represent one of the most active classes of compounds possesses wide spectrum biodynamic activities and use as potent therapeutic agents. In this research work, a synthesis, characterization and biological evaluation of 6-substituted-2-(substituted-phenyl)-quinoline derivatives bearing 4-amino-1,2,4-triazole-3-thiol ring at C-4 position is described. The synthesis of quinoline derivatives is carried out by the reaction of substituted quinoline-4-carbohydrazides with a mixture of carbon disulphide and potassium hydroxide which further react with hydrazine hydrate to give final compounds. All of these compounds were screened for their in vitro antimicrobial assay against gram (+ve), gram (-ve) bacteria and fungi activity compared with standard drugs viz., Ampicilin, Chloramphenicol, Ciprofloxacin, Norfloxacin, Griseofulvin and Nystatin at different concentrations. Keywords: Quinoline, 4-amino-1,2,4-triazole-3-thiol; therapeutic agents; antimicrobial assay 1. INTRODUCTION Tuberculosis (TB) is a global epidemic caused by various strains of mycobacterium, usually Mycobacterium tuberculosis (H37RV). Tuberculosis has been considered to be a disease of poverty for many years with quite rare occurrence in the developed countries. Unfortunately recently more people in the developed world are contracting tuberculosis because their immune systems are compromised by immunosuppressive drugs, substance abuse or AIDS. Several decades ago effective anti-TB drugs have been launched and one could hardly find a TB case to be demonstrated at the medicinal universities. But TB stroke back1. The return of tuberculosis was declared by World Health Organization (WHO) as a global emergency compared to a hypothetic third world war with 9 million new TB cases and two million deaths reported each year2,3; about one-third of the world’s population is already infected with M. tuberculosis4. International Letters of Chemistry, Physics and Astronomy 8 (2014) 30-37 The quinoline was reported to exhibit various biological activity such as antiviral5,6, antiamoebic7, anti-inflammatory8,9 as well as antimalarial10,11 activity. In addition, the discovery of nalidixic acid, a urinary tract antimicrobial drug12, prompted the synthesis of many quinoline derivatives and evaluationfor their antimicrobial activity13-15 and antibacterial activity. Norfloxacin, ofloxacin and ciprofloxacin (nalidixic acid analogs) were marketed as antibacterial agent16. Besides, triazole ring are important examples of the heteroazoles that by themselves or in combination with other ring systems possess antimicrobial17-19 as well as antibacterial activity. By keeping in view this fact, a series of substituted 4-amino-1,2,4triazole-3-thiol quinoline derivatives have been synthesized to investigate their antimicrobial activity and antitubercular activity20-24. 2. RESULT AND DISCUSSION 2. 1. Chemistry Preparation of 4-amino-5-[6-chloro/fluoro/nitro-2-(4-chloro/flouro/methylphenyl)quinolin-4-yl]-4H-1,2,4-triazole-3-thiols (4a-i) is summarized in Scheme 1. Various 6[fluoro/chloro/nitro-2-(4-chloro/flouro/methylphenyl)-quinoline)-4-carbohydrazide (3a-i) were treated with potassium hydroxide and carbon disulphide in ethanol was heated under reflux until the evolution of H2S ceases. The reaction mixture was concentrated and dissolved in water and acidified with HCl. The resulting product was treated with hydrazine hydrate in ethanol under reflux condition to give final compounds. The yields of the products were obtained in the range of 65-80 %. Designed series of molecules Scheme 1 were characterized by 1H NMR, IR and Mass spectrometry techniques before evaluating for antimicrobacterial and antitubercular activity. O OH O N 1(a-i) R O H N NH2 H2N NH2 2H2O SOCl2 R1 Cl R1 N R 2 (a-i) R1 SH N N N NH2 (i) KOH, CS2 N 3 (a-i) R (ii) H2N NH2 R1 N 4 (a-i) R= 4-Cl-C6H4, 4-F-C6H4, 4-CH3-C6H4 R1=4-F, 4-Cl, 4-NO2 Scheme 1 2. 2. Antimicrobial and antitubercular activity The products (4a-i) were assayed for their in vitro biological assay like antibacterial activity towards S. pyogens MTCC-442, S. aureus MTCC-96 (Gram positive) and E. coli MTCC-443, P. aeruginosa MTCC-424 (Gram negative) bacterial strain and antifungal activity towards A. niger MTCC-282 and A. clavatus MTCC-1323 at different concentrations: i.e. 0 (control), 5, 25, 50, 100, 250 (μg/ml) for their MIC (Minimum Inhibitory Concentration) values. The biological activities of the synthesized compounds 31 R International Letters of Chemistry, Physics and Astronomy 8 (2014) 30-37 (Xa-i) were compared with standard drugs viz., Ampicilline, Chloramphenicol, Ciprofloxacin, Norfloxacin, Griseofulvin and Nystatin. The result of antimicrobial activity is presented Table in given below bold value presented that, these compounds are biological active near or above than the standard drugs, Table 1-3. Table 1 Antibacterial activity (Zone of inhibition in m.m.) Entry R R1 4a 4b 4c 4d 4e 4f 4g 4h 4i 4-Cl-C6H4 4-Cl-C6H4 4-Cl-C6H4 4-F-C6H4 4-F-C6H4 4-F-C6H4 4-CH3-C6H4 4-CH3-C6H4 4-CH3-C6H4 S. pyogens MTCC-442 S. aureus MTCC-96 25 50 100 250 5 25 10 13 15 17 09 11 13 14 17 12 12 13 15 18 11 12 13 14 17 10 10 12 13 18 10 12 14 15 18 09 10 12 15 17 13 11 15 18 19 13 14 15 18 12 14 Comparative activity of 4(a-i) with known chosen standard drugs 4-F 4-Cl 4-NO2 4-F 4-Cl 4-NO2 4-F 4-Cl 4-NO2 Standard drug Ampicilline Chloramphenicol Ciprofloxacin Norfloxacin . 5 - 11 10 16 18 14 13 19 19 19 19 21 20 Antibacterial activity 18 19 10 13 20 20 12 14 21 22 17 19 21 21 19 22 50 11 14 14 13 12 13 12 14 13 100 15 16 15 15 14 14 15 16 15 250 18 17 18 17 16 16 17 18 18 14 19 21 25 16 20 22 26 18 21 21 28 Table 2 Antibacterial activity (Zone of inhibition in m.m.) Entry R R1 4a 4b 4c 4d 4e 4f 4g 4h 4i 4-Cl-C6H4 4-Cl-C6H4 4-Cl-C6H4 4-F-C6H4 4-F-C6H4 4-F-C6H4 4-CH3-C6H4 4-CH3-C6H4 4-CH3-C6H4 4-F 4-Cl 4-NO2 4-F 4-Cl 4-NO2 4-F 4-Cl 4-NO2 E. coli MTCC-443 5 - 25 12 15 13 11 12 10 12 12 10 50 14 16 16 12 14 14 13 15 13 100 16 15 16 16 17 15 15 19 15 P. aeruginose MTCC-424 250 17 16 19 18 19 16 21 19 19 5 - 25 13 12 13 12 10 12 11 10 13 50 14 13 14 14 12 15 13 12 14 100 16 15 15 16 13 16 15 13 15 250 20 20 17 19 16 17 18 15 19 15 18 24 21 18 19 26 23 20 21 27 23 Comparative activity of 4(a-i) with known chosen standard drugs Standard drug Ampicilline Chloramphenicol Ciprofloxacin Norfloxacin 14 14 20 22 15 17 23 25 16 23 28 26 32 Antibacterial activity 19 (...truncated)