Send Orders for Reprints to reprints@benthamscience.ae 48 Combinatorial Chemistry & High Throughput Screening, 2015, 18, 48-52 Synthesis and Antitubercular Screening of Some Novel 4H-1,4- Benzothiazines and their Sulfones Under Environment Benign Solvent Free Conditions as Future Anti-Tubercular Agents Anjali Guleria *,1 , Dinesh K. Jangid 1 , Naveen Gautam 2 , Richa Lakhotia 3 , Abhay Chowdhary 3 and Dinesh C. Gautam 1 1 Department of Chemistry, University of Rajasthan, Jaipur-302004, India 2 L.B.S Government PG College, Kotputli, Jaipur-303108, India 3 Department of Clinical Pathology, Haffkines Institute of Training, Testing and Research, Mumbai- 400 012, India Abstract: Some novel analogs of 4H-1,4-benzothiazines were synthesized under environmentally benign solvent free conditions by one pot oxidative cyclocondensation of substituted 2- aminobenzenthiols with compounds having active methylene group and then converted in to sulfones. These compounds were examined as antitubercular agents against Mycobacterium tuberculosis H37Rv using REMA plate method. The best results have MICs from 6.4 to 8.8 µg/mL, comparable to phenothiazines. IR, NMR and mass spectral investigations are included for structural elucidation. Keywords: 4H-1,4-benzothiazines, antitubercular agents, green chemistry, REMA, sulfones. INTRODUCTION Every third person in the world is infected with Mycobacterium tuberculosis (Mtb). In the last few years, the scenario got worse with increased cases of multi drug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB). XDR-TB is increasing at alarming rate. According to WHO’s latest report by September 2013, 92 countries had reported at least one XDR-TB case [1]. An urgent need to design new anti-TB drugs that can treat MDR and XDR-TB or at least shorten the treatment duration has emerged because of draining pipeline of anti-TB drugs due to MDR-TB which is resistant to first line drugs i.e. isoniazid and rifampin and XDR-TB which is resistant to first line drugs and half of the second line drugs e.g. any flouroquinolone, amikacin, kanamycin, capreomycin, etc. Phenothiazine drugs like chlorpromazine, thioridazine and trifluoroperazine are reported to have antitubercular activity [2] thus 4H-1,4-benzothiazines [3-9] can also be anticipated as anti-Tb drugs because of their structural resemblance to phenothiazines, in having fold along nitrogen sulfur axis, a structural feature responsible for its wide spectrum of pharmacological and biological activities [10- 14]. To explore this possibility for benzothiazines and its derivatives we synthesized and screened some novel compounds as antitubercular agents. The mechanism of action like other psychotropic drugs supposed to involve the direct binding of drug to type II *Address correspondence to this author at the Department of Chemistry, University of Rajasthan, Jaipur-302004, Rajasthan, India; Tel: +919596931563; E-mail: anjali.guleria86@gmail.com NADH dehydrogenase (NDH-2), a critical respiratory enzyme of Mtb encoded by ndh gene [15], as an uncompetitive inhibitor with respect to primary quinone substrate, ubiquinone Q2 and non competitive inhibitor with respect to NADH thus preventing the bacteria to respire resulting in its growth inhibition as NDH-2 is likely to be the only NADH-dehydrogenase enzyme utilized for growth in an aerobic environment in the Mtb respiratory chain [16]. This paper concentrates on the synthesis of some novel 4H-1,4-benzothiazines under solvent free environmentally benign conditions [17], their conversion in to sulfones [18- 20] and their screening as possible future anti-TB drugs by REMA plate method. The structure elucidation has been done by IR, NMR and mass spectroscopy. MATERIALS AND METHODS All the melting points were determined and are uncorrected. Infrared spectra were recorded in KBr on SHIMADZU 8400 S FTIR spectrophotometer. 1 H NMR and 13 C NMR spectra (by broad band proton decoupling technique) were recorded in DMSO-d6/CDCl3 on JEOL AL-300 spectrometer at frequencies of (300.40 MHz and 75.45 MHz) respectively. TMS (tetramethyl silane) is used as an internal standard and Chemical shifts are measured in δ, ppm. Mass spectra were recorded on JEOL SX 102/DA 600 using Xenon/Argon as FAB (Fast Atom Bombardment) gas. The purity of compounds were checked by TLC using silica gel "G" as adsorbent in various non aqueous solvent systems and visualizing these by UV light or in an Iodine chamber. Elemental analysis of these compounds was also done. 1875-5402/15 $58.00+.00 © 2015 Bentham Science Publishers