Structural hybrids of sulfonamide and thiazole moieties: Synthesis and evaluation of antimicrobial activity

Abstract For the discovery of new antimicrobial drugs, new derivatives of sulfonamide having thiazole ring were synthesized. The new series of sulfonamide derivatives were synthesized starting from 4-(arylsulfonamido)-acetophenone thiosemicarbazones 2a–f. Cyclization of thiosemicarbazone derivatives 2a–f by using ethyl chloroacetate and chloroacetone gave the thiazolidin-4-ones 3a–f and 4-methylthiazoles 4a–e, respectively. The antimicrobial properties of the synthesized compounds were investigated. The major thiosemicarbazone and thiazole derivatives gave no effect on most of the tested microorganisms. Incorporation phenyl group at both of the N-4 of thiosemicarbazones and the sulfonamide as in compound 2f gave moderate effects against most of the screened Gram-positive bacteria. Graphical Abstract


Introduction
The drug-resistant microbes have been reported as one of the medication problems. This problem may be arise due to the misuse of antibiotics or may be due to the inaccurate diagnosis. The antibiotic resistance is a major global challenge; where, many infectious diseases that caused by resistant organisms do not recover from ordinary antibiotics. To overcome this problem or reduce the adverse effects, many strategies were created, such as create novel pharmacophore. A lot of research was directed to combine two or more pharmacophoresthis to get a powerful synergistic effect in one molecular structure. [1][2][3][4][5] After the discovery of sulfonamide as bacteriostatic drugs, the sulfonamide groups were important components in medicinal chemistry researches and applications. [6][7][8] Recently, sulfonamide derivatives have varieties of biological properties, such as antimicrobial, [7,9] anticancer, [6] antiviral, [10] anti-inflammatory, [11] antioxidant, [12] Alzheimer diseases, [13] carbonic Anhydrase inhibitor, [14,15] Up to date, many sulfonamide-based drugs have been approved by FDA and still available in the markets. [16] The diverse pharmacological activity of sulfonamides put it in the first choice for the hybridization approach. Recently, the hybridization of sulfonamide moiety with heterocycles have been successfully developed. [17][18][19][20] Thiazole ring was appeared in many structures of natural compounds and some of the synthesized biologically active agents. Thiazole nucleus constitutes an interesting class of bioactive molecules where its exhibits broad spectra of biological activities, such as anti-inflammatory, [21] anticonvulsant, [8] antimicrobial, [2,22] anticancer, [23] and anti-HIV. [24] Thiazole ring plays a conclusive role in the drug discovery research, Thiazole ring has therapeutic properties for several diseases. Some examples of thiazole-based drugs are thiamethoxam (insecticide), nizatidine (antiulcer agent), fanetizole (antiinflammatory agent), meloxicam (anti-inflammatory agent), fentiazac (anti-inflammatory agent), nitazoxanide (antiparasitic agent), ravuconazole (antifungal agent), ritonavir (anti-HIV), Tiazofurin (antineoplastic agent) and dasatinib (antineoplastic agent). [22] Depending on our experience in thaizole synthesis, [25][26][27] we aim to synthesize a series of sulfonamides bearing thiazole nucleus through methylenehydrazono linker. Where thiosemicarbazone derivatives will subject to cycloalkylation with ethyl chloroacetate and chloroacetone in the hope of obtaining thiazoles with potent antimicrobial effect.

Results and discussion
The 4-(arylsulfonamido)-acetophenone thiosemicarbazones 2a-f as starting materials were synthesized as displayed in Scheme 1. At first, 4-(arylsulfonamido)-acetophenone 1a,b were prepared in good yields by using a reported procedure with some modification. [28] The 4-(arylsulfonamido)-acetophenones 1a,b were easily obtained by the nucleophilic reactions of 4-aminoacetophenone with methane sulfonyl chloride or benzene sulfonyl chloride. Thiosemicarbazones of 4-(arylsulfonamido)-acetophenone were prepared through the condensation reactions between 4-(arylsulfonamido)-acetophenones 1a-f and some thiosemicarbazide derivatives under reflux condition in ethyl alcohol containing catalytic amount of acetic acid. As representative of the formed thiosemicarbazones 2a-f, 1 H NMR spectrum of thiosemicarbazone derivative 2b displayed three diagnostic aliphatic signals for three methyl groups at: 2.28, 3.02, and 3.05 ppm. The phenylene AB protons were assigned as two doublet signals at 7.24 and 7.92 ppm with integral value for two protons Beside the aliphatic and aromatic protons, 1 H NMR spectrum reveals three signals for NH groups at d ¼ 8.41, 9.92, and 10.17. 13 C NMR spectrum of compound 2b showed three diagnostic aliphatic signals at: 14.27, 31.53, and 38.53 ppm were assigned for three methyl groups. The signal at: 179.04 ppm was assigned for C¼S.
One of the efficient methods for the creation of thiazole ring is the ring closure of thioamide derivatives with halogenated compounds. [22,23] So, Thiosemicarbazone derivatives 2a-f were cyclized with two different halogenated compounds. The thiosemicarbazone derivatives 2a-f were left to react with ethyl chloroacetate in THF under reflux conditions resulting from the formation of the thiazolidone derivatives 3a-f in good yields (Scheme 2). The formation of thiazolidone derivatives 3a-f is initially proceed via alkylation of the thiosemicarbazone derivatives to give intermediate A which is followed by intramolecular cyclization with the elimination of ethanol. 1 H NMR spectrum of thiazolidone derivative 3b reveals four diagnostic aliphatic signals for three methyl groups and CH 2 -thiazole at: 2.40, 3.04, 3.20, and 3.93 were assigned. The phenylene protons were assigned as two doublet signals at 7.27 and 7.84 ppm. Finally, 1 H NMR spectrum displayed one signal for NH group at d ¼ 10.08. 13 C NMR spectrum of thiazole 3b reveals three diagnostic aliphatic signals due to three methyl group and one signal for CH 2 of thiazole. Signals for phenyl carbons were observed at: 119.18 (2CH), Similar to the above reaction condition, cyclocondensation of thiosemicarbazone derivatives 2a-f with chloroacetone was took place and furnished the derivatives of 4methyl-2,3-dihydrothiazole 4a-f. Like the above reaction, the formation of thiazolidone derivatives 4a-f is begin through alkylation of thiosemicarbazones to give intermediate B which followed by intramolecular cyclization with the elimination of water. As representative to the formed thiazoles 4a-f, 1 H NMR spectrum of thiazole derivative 4a displayed three diagnostic aliphatic signals for three methyl groups at: 2.17, 2.25, and 3.02. The diagnostic H-5 proton of thiazole has appeared at d ¼ 6.32 ppm. The phenylene protons were assigned as two doublet signals at 7.23 and 7.72 ppm. Finally, 1 H NMR spectrum displayed two signals for 2NH groups at: d ¼ 9.87 and 10.97 ppm.
Few derivatives showed good effects on some of the microorganisms. The major derivatives gave no effects on most microorganisms. Certain aspects can be clearly highlighted. The 4-(arylsulfonamido)-acetophenone thiosemicarbazones 2a-f have different substituents at N-atom and sulfonamide group. the property effects of each substituent were investigated. The incorporation of methyl group at both of the N-4 of thiosemicarbazones and the sulfonamide as in compound 2b gave effects against the tested fungus organism only. Incorporation phenyl group at both of the N-4 of thiosemicarbazones and the sulfonamide as in compound 2f gave effects against most of the screened Gram-positive bacteria. The antimicrobial activity of compounds 3a-f and 4a-f with different substituents at the nitrogen atom of thiazole and at sulfonamide group was investigated. Closure of the derivatives of the thiosemicarbazone 2a-f with ethyl chloroacetate to give the thiazoles 3a-f does not improve the antimicrobial activity. Only thiazole 3a gave effects against the tested MRSA organisms only. Also, the thiazoles 4a-f did not give antibacterial activity. Only thiazole 4a,b gave effect against the tested Candida albicans organisms only.

Synthesis of 4-(arylsulfonamido)-acetophenone thiosemicarbazones 2a-f
A mixture of equimolar amounts (0.01 mol) of N-(4-acetylphenyl)methane-(or benzene)-sulfonamide (1a,b) and the selected thiosemicarbazides (thiosemicarbazide, Nmethyl-thiosemicarbazide, and N-phenylthiosemicarbazide) was heated under reflux in a mixture of 1 mL AcOH and 50 mL ethyl alcohol for 0.5 h. The resultant solid crystals were collected recrystallized from THF. Synthesis of the derivatives of 4-phenyl-2,3-dihydrothiazole 4a-f The mixture of 0.001 mol of the thiosemicarbazones 2a-f, 0.01 mole of choloroacetone, and 0.002 mol of fused CH 3 COONa was gently heated in 40 mL THF (in case of 2d excess solvent was used). The solution of the reaction mixture was heated under reflux conditions for 6 h. Then, it was concentrated. After cooling, the obtained crude products were collected and recrystallized from ethyl alcohol to give 4-phenyl-2,3-dihydrothiazole derivatives 4a-f.