Synthesis and in-vitro studies of some new quinoline 1,3,4-thiadiazolo pyrimidin derivatives

Bull. Chem. Soc. Ethiop. 2017, 31(2), 337-344.  2017 Chemical Society of Ethiopia and The Authors DOI: http://dx.doi.org/10.4314/bcse.v31i2.15 ISSN 1011-3924 Printed in Ethiopia SYNTHESIS AND IN-VITRO STUDIES OF SOME NEW QUINOLINE 1,3,4THIADIAZOLO PYRIMIDIN DERIVATIVES Kishore Kumar Valluri1, I.V. Kasi Viswanath1*, P.V.V.S. Naga Raju1, B. Rajasekher2 and B. Rama Dasu1 1 Department of Chemistry, K.L. University, Green Fields, Vaddeswram, Guntur, A.P, India 2 Vasudha Pharmaceuticals, Visakhapatnam, India (Received April 7, 2016; revised August 22, 2017) ABSTRACT. A series of eight new quinoline associated 1,3,4-thiadiazolo pyrimidin derivatives (5a-h) have been developed using 4-amino-8-fluoro-quinoline-3-carboxylic acid ethyl ester (1) as raw material and by involving 8-fluoro-4-methylsulfanylthiocarbonylamino-quinoline-3-carboxylic acid ethyl ester (2), 8-fluoro-4hydrazine thiocarbonylamino-quinoline-3-carboxylic acid ethyl ester (3) and 3-amino-7-fluoro-2-mercapto-3Hpyrimido-[5,4-c]quinolin-4-one (4) as intermediates. The title compounds after structure elucidation were used in vitro to find their antibacterial ability towards different micro-organisms. KEY WORDS: Synthesis, Quinoline, 1,3,4-thiadiazolo pyrimidin, Spectral data, Potential activity INTRODUCTION The quinoline skeleton is often used for the design of many synthetic compounds with diverse pharmacological properties such as anti-inflammatory [1], antimicrobial [2], cytotoxic [3], antitumor [4], antimalarial [5], anti-cancer [6], HIV protease inhibitor [7] and anti-viral [8] activities. It is known that many 1,3,4-thiadiazoles have biological activities like antibacterial [9], antimycobacterial [10], antimycotic [11], antifungal [12], antidepression [13], analgesic [14] and anti-inflammatory [15]. Nitrogen containing heterocyclic ring such as pyrimidine and its derivatives have been reported as anti-microbial [16], analgesic, anti-viral, anti-inflammatory [17], anti-HIV [18], anti-tubercular [19], anti-tumour [20], anti-neoplastic [21], anti-malarial [22], diuretic [23], cardiovascular [24] agents. S S NH2 O NH O 1 N F O NH O (i) 2 F H N NH 2 S O N 3 NH2 O (iii) H N R 4 N N F N N O (ii) SH F (iv) S N N N O N F 5a-h Scheme 1. (i) CS2, NaOH, DMSO, RT, 2 h; (ii) NH2-NH2, EtOH, reflux, 6 h; (iii) EtOH, reflux, 4 h; (iv) ArNCS, K2CO3, DMF, reflux, 20-22 h 5 (a-h): R = a) C6H5; b) 4-CH3-C6H4; c) 3-OCH3-C6H4; d) 4-OCH3-C6H4; e) 3-Cl-C6H4; f) 4-Cl-C6H4; g) 3NO2-C6H4; h) 4-NO2-C6H4. __________ *Corresponding author. E-mail: This work is licensed under the Creative Commons Attribution 4.0 International License 338 Kasi Viswanath et al. Here in, we report a series of eight new quinoline associated 1,3,4-thiadiazolo pyrimidin derivatives. Compound 5e displayed activity more than standard benzyl pencillin against B. subtilis and considerable activity against streptomycin, and compounds 5b and 5f are significant active towards M. luteus compared to standard drug. The general synthetic scheme is presented in Scheme 1. EXPERIMENTAL All the reagents and solvents were used as purchased without further purification. Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. IR spectra were obtained on a Perkin-Elmer BX serried FTIR 5000 spectrometer using KBr pellet. NMR spectra were recorded on a Varian 300 MHz spectrometer for 1H-NMR and 100 MHz for 13 C-NMR. The chemical shifts were reported as ppm down field using TMS as an internal standard. Mass spectra were recorded on a VG-Micromass 7070H spectrometer operating at 70 eV. The antimicrobial studies were conducted by broth method. The broth culture is incubated in non-CO2 incubator at 35 oC until it achieves or exceeds the turbidity of the 0.5 McFarland standard (usually 2 to 6 hours). By obtaining isolated colonies of bacterial strains to test and combine the colonies and culture in rich media, incubate overnight and count colonies. The turbidity of the actively growing broth culture is adjusted with sterile saline or broth to obtain a turbidity optically comparable to that of the 0.5 McFarland standard and verified cfu/mL count of visible media and the collective results were noted. Synthesis of 8-fluoro-4-methylsulfanylthiocarbonylamino-quinoline-3-carboxylic acid ethyl ester (2) To a mixture of 4-amino-8-fluoro-quinoline-3-carboxylic acid ethyl ester (1) (0.01 mol) in dimethyl sulphoxide (10 mL) at room temperature was added carbon disulfide (1.4 mL) and aqueous sodium hydroxide (1.0 mL) solution in drop wise. After 30 min dimethyl sulfate (2.3 g) was added under cold conditions by keeping in an ice bath. The reaction mixture then constantly stirred at room temperature for 1.5 h. After completion of the reaction (monitored by TLC), the resultant solution was poured in ice water. The solid that separated out was filtered, dried and recrystallized from ethanol to get pure 8-fluoro-4-methylsulfanylthiocarbonylamino-quinoline3-carboxylic acid ethyl ester (2). Synthesis of 8-fluoro-4-hydrazine thiocarbonylamino-quinoline-3-carboxylic acid ethyl ester (3) To the mixture of 8-fluoro-4-methylsulfanylthiocarbonylamino-quinoline-3-carboxylic acid ethyl ester (2) (0.01 mol) in ethanol (10 mL) was added hydrazine hydrate (15 mL) and the resulted solution was refluxed for 6 h on uniform stirring. After completion of the reaction (examined by TLC), the mixture was cooled to room temperature, poured in ice-cold water (15 mL) and filtered. The obtained crude solid was recrystallized from ethanol to give 8-fluoro-4hydrazine thiocarbonylamino-quinoline-3-carboxylic acid ethyl ester (3). Synthesis of 3-amino-7-fluoro-2-mercapto-3H-pyrimido-[5,4-c]quinolin-4-one (4) A mixture of 8-fluoro-4-hydrazine thiocarbonylamino-quinoline-3-carboxylic acid ethyl ester (3) (0.01 mol) in ethanol (10 mL) was heated under reflux with steady stirring for 4 h. After completion of the reaction (watched by TLC), the residual mass was poured over crushed ice and the precipitated crude product was filtered, washed with water, dried and recrystallized from ethanol to get the pure 3-amino-7-fluoro-2-mercapto-3H-pyrimido-[5,4-c]quinolin-4-one (4). Bull. Chem. Soc. Ethiop. 2017, 31(2) Synthesis of some new quinoline 1,3,4-thiadiazolo pyrimidin derivatives 339 Synthesis of 2-arylamino-8-fluoro-[1,3,4]thiadiazolo-[3,2-a]pyrimidin-[5,4-c]quinolin-5-ones (5a-h) A mixture of 3-amino-7-fluoro-2-mercapto-3H-pyrimido-[5,4-c]quinolin-4-one (4) (0.01 mol), small amount of anhydrous potassium carbonate and suitable aryl isothiocyantes in DMF (15 mL) was refluxed with consistent stirring for 20-22 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and poured in crushed ice. The resulted solid was filtered off. The crude product thus obtained was purified by column chromatography on silica gel with hexane-ethyl acetate as eluent to afford corresponding 2-arylamino-8-fluoro-[1,3,4]thiadiazol (...truncated)