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

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.


INTRODUCTION
Tuberculosis (TB) is a global epidemic caused by various strains of mycobacterium, usually Mycobacterium tuberculosis (H 37 RV). 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 back 1 . 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 year 2,3 ; about one-third of the world's population is already infected with M. tuberculosis 4 .
The quinoline was reported to exhibit various biological activity such as antiviral 5,6 , antiamoebic 7 , anti-inflammatory 8,9 as well as antimalarial 10,11 activity. In addition, the discovery of nalidixic acid, a urinary tract antimicrobial drug 12 , prompted the synthesis of many quinoline derivatives and evaluationfor their antimicrobial activity [13][14][15] and antibacterial activity. Norfloxacin, ofloxacin and ciprofloxacin (nalidixic acid analogs) were marketed as antibacterial agent 16 . Besides, triazole ring are important examples of the heteroazoles that by themselves or in combination with other ring systems possess antimicrobial [17][18][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 activity 20-24 .

Antimicrobial and antitubercular activity
The products (4a-i) were assayed for their in vitro biological assay like antibacterial activity towards S.  Table in given below bold value presented that, these compounds are biological active near or above than the standard drugs, Table 1-3.   All compounds were initially screened for their antitubercular activity at 6.25 μg/mL concentration against MTB H37Rv strain by the Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF) in BACTEC 12B medium using the Microplate Alamar Blue Assay 20 .

EXPERIMENTAL SECTION
All research chemicals were purchased from Sigma-Aldrich and used as such for the reactions. Reactions were monitored by thin-layer chromatography (TLC) on pre-coated silica gel GF254 plates from E-Merck Co and compounds visualized either by exposure to UV light or staining with reagents. Melting points were determined in open capillaries and are uncorrected. The IR spectra were recorded on SHIMADZU-FTIR-8400 spectrophotometer using KBr pellet method. 1 H NMR spectra were recorded on Bruker 300-MHz NMR spectrometer in CDCl 3 with TMS as internal standard. Mass spectrum was recorded on JOEL SX 102/DA-600-Mass spectrometer and elemental analysis was carried out using Heraus C, H, and N rapid analyzer

CONCLUSIONS
In the present paper, we report the synthesis, spectral studies and its antimicrobial and antimycobacterial activity of various quinoline derivatives. The high bioactivity of these compounds makes them suitable hits for additional in vitro and in vivo evaluations, in order to develop new class of antimicrobial and antimycobacterial drugs or prodrugs with potential use in the antibacterial, antifungal and tuberculosis treatment. Further studies in this area are in progress in our laboratory.

ACKNOWLEDGEMENT
Authors are thankful to the Director, SAIF-Chandighar and CDRI Lucknow (U.P.) for recording various spectral data and special thanks to TAACF to conduct Antitubercular activity. Authors also thankful to Microcare laboratories, Surat for antimicrobial activity of (4a-i). and also to Professor and Head, Department of Chemistry, Saurashtra University-Rajkot for providing necessary laboratory facilities.