Design, Synthesis, Characterization and Computational Docking Studies of Novel Sulfonamide Derivatives

EXCLI Journal 2018;17:169-180 – ISSN 1611-2156 Received: October 17, 2017, accepted: January 29, 2017, published: February 01, 2018 Original article: DESIGN, SYNTHESIS, CHARACTERIZATION AND COMPUTATIONAL DOCKING STUDIES OF NOVEL SULFONAMIDE DERIVATIVES Hira Saleem1a, Arooma Maryam1a, Saleem Ahmed Bokhari1a, Ayesha Ashiq1, Sadaf Abdul Rauf2, Rana Rehan Khalid1, Fahim Ashraf Qureshi1b, Abdul Rauf Siddiqi1 ⃰ 1 Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan 2 Department of Computer Science, Fatima Jinnah Women University, The Mall, Rawalpindi a Equal contributions, co-first authors b Shared correspondence: [email protected] ⃰ corresponding author: Abdul Rauf Siddiqi, Department of Biosciences, COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan E-mail: [email protected], [email protected] http://dx.doi.org/10.17179/excli2017-886 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). ABSTRACT This study reports three novel sulfonamide derivatives 4-Chloro-N-[(4-methylphenyl) sulphonyl]-N-propyl benzamide (1A), N-(2-hydroxyphenyl)-4-methyl benzene sulfonamide (1B) and 4-methyl-N-(2-nitrophenyl) benzene sulfonamide (1C). The compounds were synthesised from starting material 4-methylbenzenesulfonyl chloride and their structure was studied through 1H-NMR and 13C-NMR spectra. Computational docking was performed to estimate their binding energy against bacterial p-amino benzoic acid (PABA) receptor, the dihydropteroate synthase (DHPS). The derivatives were tested in vitro for their antimicrobial activity against Gram+ and Gram- bacteria including E. coli, B. subtilis, B. licheniformis and B. linen. 1A was found active only against B. linen; 1B was effective against E. coli, B. subtilis and B. linen whereas 1C showed activity against E. coli, B. licheniformis and B. linen. 1C showed maximum activity with minimum inhibitory concentration (MIC) of 50, 100 and 150 µg/mL against E. coli, B. licheniformis and B. linen respectively. 1C exhibited maximum affinity to DHPS with binding free energy of -8.1 kcal/mol. It enriched in the top 0.5 % of a library of 7663 compounds, ranked in order of their binding affinity against DHPS. 1C was followed by 1B which showed a moderate to low level MIC of 100, 250 and 150 µg/mL against E. coli, B. subtilis and B. linen respectively, whereas 1A showed a moderate level MIC of 100 µg/mL but only against B. linen. These derivatives may thus serve as potential antibacterial alternatives against resistant pathogens. Keywords: Sulfonamide, derivatives, synthesis, antimicrobial, activity, structure INTRODUCTION are posing substantial economic and health Antibiotic resistance is an inevitable evo- threats globally (Sengupta et al., 2013; lutionary phenomenon which renders antimi- Lushniak, 2014). Microbes have evolved crobial products ineffective against infec- various intrinsic mechanisms enabling them tions. Antibiotic resistant microbial strains to develop antibiotic resistance specific to structural and functional features of 169 EXCLI Journal 2018;17:169-180 – ISSN 1611-2156 Received: October 17, 2017, accepted: January 29, 2017, published: February 01, 2018 antibiotics (Sengupta et al., 2013). They ac- considered as first best option (Sławiński et quire resistance against active drugs through al., 2013). Growing concern associated with spontaneous mutations and horizontal gene antibiotic resistance has spurred further re- transfer. Overuse of antibiotics gradually search for more selective and efficacious an- eliminates drug-sensitive strains leaving be- timicrobial solutions. To that effect, a rela- hind drug resistant species to survive and re- tively direct and cost effective strategy for produce as a consequence of natural selec- drug discovery is ligand based design, which tion (Randall et al., 2013). involves designing new therapeutic mole- Sulfonamides have long been in use as cules based on structural and functional effective therapeutic agents against both properties of already known drugs. The nov- Gram+ and Gram- bacterial strains associat- el derivatives improve basic structural and ed with a range of infectious diseases (Nasr functional therapeutic attributes while decoy- et al., 2016). These broad spectrum synthetic ing pathogen’s resistance mechanism. drug molecules compete with and inhibit the Here we report three novel sulfonamide binding of p-amino benzoic acid (PABA) in derivatives, their mode of synthesis, physico- binding site of dihydropteroate synthase chemical properties, structure, binding affini- (DHPS) enzyme thereby interfering with the ties with DHPS, activity and Minimum In- vital bacterial dihydrofolic acid synthesis hibitory Concentration (MIC) against a set of pathway (Seydel, 1968; Argyropoulou et al., Gram- and Gram+ bacteria. These novel de- 2009). In bacteria, folic acid is an essential rivatives are listed below (Table 1). component required for DNA and RNA synthesis. By disrupting folic acid synthesis MATERIALS AND METHODS pathway in bacterial cell, sulfonamides com- Structure of DHPS promise the microbes’ ability to divide and Structure of dihydropteroate synthase reproduce. In addition to being antibacterial, (DHPS) enzyme of Escherichia Coli, de- sulfonamides and their derivatives are wide- termined through X-Ray Crystallography, ly prescribed as insulin release inducers, an- solved at 2.00Å resolution (PDB: 1AJ0) al- tiviral, antifungal, anti-cancer and anti- ready bound with a sulfonamide ligand inflammatory agents (Bano et al., 2011; (C6H8N2O2S) was selected as target and re- Zoumpoulakis et al., 2012; Sławiński et al., trieved from RCSB’s PDB database 2013). (Achari et al., 1997). DHPS sulfonamide However, bacteria have developed re- pocket is configured by H bond forming sistance against popular sulfonamide based Ser219, Arg220, and Arg63 and aromatic drugs such as co-trimoxazol and sulfameth- Pro64, Phe190, Phe157 and Pro232 residues oxazole etc. Owing to the rise of resistance (Figure 1). against sulfonamides in a number of bacterial pathogens, the sulfonamides are hardly Table 1: Sulfonamide derivatives synthesized in this study IUPAC Name Code Chemical Group 4-chloro-N-[(4-methylphenyl)sulfonyl]-N-propyl benzamide 1A Sulfonamide N-(2-hydroxyphenyl)-4-methyl benzenesulfonamide 1B Sulfonamide 4-methyl-N-(2-nitrophenyl) benzenesulfonamide 1C Sulfonamide 170 EXCLI Journal 2018;17:169-180 – ISSN 1611-2156 Received: October 17, 2017, accepted: January 29, 2017, published: February 01, 2018 Figure 1: (a) Structure of Escherichia coli Dihydropteroate Synthase (DHPS), PDB: 1AJ0 (8). A sulfonamide molecule (C6 H8 N2 O2 S) molecule is bound inside the binding pocket. (b) Zoomed in binding pocket of DHPS shown in transparent surface, the sidechains of the residues configuring the binding pocket and imparting the polar and nonpolar interactions on sulfonamide molecule are labelled, three green dashed lines show hydrogen bonds with Arg 63, Ser219 and Arg 220. Structure and physical properties of Sul- Synthesis and structure of 4-Chloro-N-[(4- fonamide derivatives methylphenyl) sulfonyl]- N-propyl ben- The structures of newly synthesized zamide (1A) compounds were determined through NMR 1A was obtained by reacting propan-1- spectroscopy and mass spectrometry. The amine with 4-methylbenzenesulfonyl chlo- spectra were recorded on a Bruker DPX-400 ride at first followed by reaction with 3- NMR spectrometer (Billerica, USA) (400 chlorobenzoyl chloride (Figure 2). Briefly, MHz for 1 13 H and 100 MHz for C-NMR), 2.5 M solution of the propylamine (propan- 3 as the solvent. The physical using CDCl 1-amine) was prepared in distilled water. The properties were also determined and charac- solution was added to 0.44 M p-toluene sul- terized by FT-IR and Elemental analysis fonyl chloride (4-methylbenzenesulfonyl (CHNS). chloride). The mixture was stirred slowly for 2-3 hours while maintaining pH during the Synthesis of Sulfonamide derivatives reaction between 6-10 with 3 % Na2CO3. N- In view of already known structure activ- propyl benzenesulfonamide thus formed was ity relationship of sulfonamide derivatives, further reacted with 3-chlorobenzoyl chlo- three derivatives of sulfonamide were pre- ride to obtain precipitates of 4-chloro-N-[(4- pared through substitution reactions with p- methylphenyl) sulfonyl]-N-propyl ben- toluene sulfonyl chloride as detailed below. zamide. The precipitates were then filtered and washed with cold water. TLC was performed using the mixture of ethyl acetate and n-hexane (1:4) as mobile phase. 171 EXCLI Journal 2018;17:169-180 – ISSN 1611-2156 Received: October 17, 2017, accepted: January 29, 2017, published: February 01, 2018 Figure 2: (a) Reaction of propan-1-amine with 4- methylbenzenesulfonyl chloride to produce 4- methyl-N-propylbenzene- sulfonamide, (b) 4-methyl- N-propylbenzenesulfona- mide was further reacted with 3-chlorobenzoyl chloride to obtain 4-chloro-N- [(4-methylphenyl) sulfonyl]-N-propylbenzamide. Crystalline form of compound 1A as off Synthesis and structure of N-(2- white powder (93 % yield) was obtained hydroxyphenyl)-4-methyl benzenesulfona- with following physical properties: molecu- mide (1B) lar weight (351.85), molar refractivity 1B was synthesized by reacting 2- (92.25±0.4 cm3), molar volume (275.6±3.0 3 3 aminophenol with 4-methylbenzenesulfonyl cm ), parachor (724.3±6.0 cm ), index of re- chloride, TLC was performed

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