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Article

Synthesis of Novel Benzenesulfonamide-Bearing Functionalized Imidazole Derivatives as Novel Candidates Targeting Multidrug-Resistant Mycobacterium abscessus Complex

by
Benas Balandis
1,
Povilas Kavaliauskas
1,2,3,4,5,*,
Birutė Grybaitė
1,
Vidmantas Petraitis
2,4,5,
Rūta Petraitienė
2,4,
Ethan Naing
2,
Andrew Garcia
2,
Ramunė Grigalevičiūtė
5 and
Vytautas Mickevičius
1
1
Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų Rd. 19, LT-50254 Kaunas, Lithuania
2
Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, 1300 York Ave., New York, NY 10065, USA
3
Institute for Genome Sciences, School of Medicine, University of Maryland Baltimore, 655 W. Baltimore Street, Baltimore, MD 21201, USA
4
Institute of Infectious Diseases and Pathogenic Microbiology, Birštono Str. 38A, LT-59116 Prienai, Lithuania
5
Biological Research Center, Lithuanian University of Health Sciences, Tilžės Str. 18/7, LT-47181 Kaunas, Lithuania
*
Author to whom correspondence should be addressed.
Microorganisms 2023, 11(4), 935; https://doi.org/10.3390/microorganisms11040935
Submission received: 4 March 2023 / Revised: 27 March 2023 / Accepted: 1 April 2023 / Published: 3 April 2023
(This article belongs to the Special Issue Advances in Antibiotic and Antifungal Resistance and Related Alternative Therapies)
Browse Figure
Review Reports Versions Notes

Abstract

:
Infections caused by drug-resistant (DR) Mycobacterium abscessus (M. abscessus) complex (MAC) are an important public health concern, particularly when affecting individuals with various immunodeficiencies or chronic pulmonary diseases. Rapidly growing antimicrobial resistance among MAC urges us to develop novel antimicrobial candidates for future optimization. Therefore, we have designed and synthesized benzenesulfonamide-bearing functionalized imidazole or S-alkylated derivatives and evaluated their antimicrobial activity using multidrug-resistant M. abscessus strains and compared their antimycobacterial activity using M. bovis BCG and M. tuberculosis H37Ra. Benzenesulfonamide-bearing imidazole-2-thiol compound 13, containing 4-CF3 substituent in benzene ring, showed strong antimicrobial activity against the tested mycobacterial strains and was more active than some antibiotics used as a reference. Furthermore, an imidazole-bearing 4-F substituent and S-methyl group demonstrated good antimicrobial activity against M. abscessus complex strains, as well as M. bovis BCG and M. tuberculosis H37Ra. In summary, these results demonstrated that novel benzenesulfonamide derivatives, bearing substituted imidazoles, could be further explored as potential candidates for the further hit-to-lead optimization of novel antimycobacterial compounds.

1. Introduction

Infections caused by nontuberculous mycobacteria (NTM) remain a challenging and emerging public health threat, particularly in individuals undergoing chemotherapy or patients with underlying lung conditions [1]. The incidence of infections caused by NTM is increasing globally, and it can be challenging to diagnose and treat due to the diverse range of NTM species and varying patterns of antibiotic susceptibility. In addition, some NTM developed resistance to multiple antibiotics, making the infections caused by NTM difficult to treat and worsening the treatment prognosis [2,3,4]. Therefore, it is critical to develop novel small molecule antimicrobial candidates targeting NTM in particularly multidrug-resistant (MDR) strains.
Mycobacterium abscessus (M. abscessus) complex (MABC) is responsible for the majority of MDR NTM infections. MABC, consisting of genetically and phylogenetically related subspecies M. abscessus subsp. abscessus, massiliense, and bolletii, which often harbor multiple instinctive and acquired antimicrobial resistance determinants, as well as numerous virulence factors, make M. abscessus a clinically important pathogen [5]. Treatment or management of infections caused by M. abscessus requires long-term-to-lifetime treatment using multiple antibiotics. The treatment regime and duration is highly dependent on susceptibility of M. abscessus to macrolides [6]. Macrolide-susceptible M. abscessus infections require treatment using combinations of parenteral and inhalable antibiotics, which follows a maintenance period with at least three different inhalable and/or systemic antibiotics [7]. Macrolide-resistant MABC infections require a prolonged treatment duration, as well as an increased number of antibiotics, consequently making these infections extremely challenging. Therefore, it is crucial to discover novel candidates targeting MDR NTM with increased focus on M. abscessus [8].
Benzenesulfonamide scaffold have been widely used as a potent pharmacophore in medicinal chemistry [9,10]. Benzenesulfonamide nucleus-containing derivatives are widely explored in medicinal chemistry due to their ability to modulate various biological targets [11,12,13,14,15,16]. The sulfonamide group in the scaffold can act as a hydrogen bond acceptor and donor, providing a versatile platform for molecular modifications and improving the pharmacokinetic and pharmacodynamic properties of the targeted molecule. The benzene ring, on the other hand, is hydrophobic and contributes to the lipophilicity of the molecule. This can enhance the biologically active compound’s ability to penetrate cell membranes or lipid layers that are found on the cell wall of various mycobacteria. Moreover, benzenesulfonamide derivatives have been previously reported to be good inhibitors of carbonic anhydrases (CAs) [17,18,19] and therefore exhibiting antimicrobial or anticancer activity. Moreover, CAs in M. abscessus have been previously reported to be a promising antimicrobial target since the pharmacological or molecular inhibition of CAs in M. abscessus leads to defective growth or virulence [20,21,22,23]. Therefore, benzenesulfonamide nucleus-bearing compounds could be attractive scaffolds for antimicrobial discovery targeting NTM.
Imidazole is a common heterocyclic scaffold that is often found in many natural and synthetic bioactive compounds and approved drugs. Molecules containing imidazole moiety can possess a wide variety of biological properties [24,25,26,27,28,29,30,31]. Structurally, imidazole can be further chemically modified with numerous substituents, making imidazole an extremely versatile scaffold [32,33,34]. Moreover, substituting a hydrophobic group at position 2 of the imidazole ring can improve the compound’s lipophilicity, which can increase its membrane permeability and enhance the activity of antimicrobial compounds bearing an imidazole nucleus against mycobacteria.
In this study, we have synthesized novel benzenesulfonamide moiety-bearing functionalized imidazole derivatives containing various S-alkyl substituents and evaluated their antimicrobial activity against drug-resistant M. abscessus complex strains.

2. Materials and Methods

2.1. Reagents and Equipment Used for Synthesis and Characterization of Compounds

Reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA). The melting points were determined on a MEL-TEMP (Electrothermal, Bibby Scientific Company, Burlington, NJ, USA) melting point apparatus and were uncorrected. IR spectra (ν, cm−1) were recorded on a Perkin–Elmer Spectrum BX FT–IR spectrometer using KBr pellets. The 1H and 13C NMR spectra were recorded in DMSO-d6 medium on Brucker Avance III (400, 101 MHz) spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) calibrated from TMS (0 ppm) as an internal standard for 1H NMR, and DMSO-d6 (39.43 ppm) for 13C NMR. Elemental analysis was performed on a CE-440 elemental analyzer (Exeter Analytical Inc., North Chelmsford, MA, USA). The reaction course and purity of the synthesized compounds were monitored by TLC using aluminium plates precoated with silica gel 60 F254 (MerckKGaA, Darmstadt, Germany).

2.2. Synthesis

Complete synthesis of compounds 2, 4, 5, 7, and 8, as well as compounds 9, 11, 12, 14, 15, 18b was described in our previous study [35] and were resynthesized accordingly in this study. These compounds were further used for S-alkylation reactions. All of spectra data on compounds 2, 4, 5, 7, and 8 as well as compounds 9, 11, 12, 14, 15, 18b was described in our previous publication [35].
General procedure for the synthesis of compounds 3 and 6.
Amine 1 (1.72 g, 10 mmol) was dissolved in boiling water (40 mL). Then, the solution of corresponding α-haloketone (12 mmol) in 10 mL of 1,4-dioxane was added dropwise to the mixture. The reaction mixture was heated at reflux for 2 h, then it was cooled down and the precipitate was filtered off, washed with diethyl ether, and recrystallized from 1,4-dioxane to afford compounds 3 and 6.
3-((2-(4-bromophenyl)-2-oxoethyl)amino)benzenesulfonamide (3). White solid, yield 3.12 g (85%); m.p. 236–237 °C; IR (KBr) (v, cm−1): 3382, 3262, 1692; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 4.72 (s, 2H, CH2), 6.40 (br. s, 1H, NH), 6.84 (dd, 1H, J = 8.1, 2.3, Har), 7.01 (d, 1H, J = 7.6, Har), 7.11 (br. s, 1H, Har), 7.18 (br. s, 2H, NH2), 7.23 (t, 1H, J = 7.9 Hz, Har), 7.79 (d, 2H, J = 8.1 Hz, Har), 8.00 (d, 2H, J = 8.1 Hz, Har); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 49.96, 109.00, 112.96, 115.28, 127.68, 129.23, 129.93, 131.87, 134.04, 144.75, 148.49, 195.66; Anal. Calcd. for C14H13BrN2O3S: C 45.54; H 3.55; N 7.59 %. Found: C 45.57; H 3.55; N 7.54 %.
3-((2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)amino)benzenesulfonamide (6). White solid, yield 2.97 g (83%); m.p. 228–229 °C; IR (KBr) (v, cm−1): 3390, 3268, 1698; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 4.81(s, 2H, CH2), 6.44 (br. s, 1H, NH), 6.84 (d, 1H, J = 7.7, Har), 7.03 (d, 1H, J = 7.7, Har), 7.13 (br. s, 1H, Har), 7.19 (br. s, 2H, NH2), 7.24 (t, 1H, J = 7.9 Hz, Har), 7.95 (d, 2H, J = 8.0 Hz, Har), 8.26 (d, 2H, J = 8.0 Hz, Har); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 50.03, 109.06, 113.05, 115.29, 122.42, 125.13, 125.73, 125.77, 125.80, 125.84, 128.78, 129.26, 138.28, 144.78, 148.47, 196.02; Anal. Calcd. for C15H13F3N2O3S: C 50.28; H 3.66; N 7.82 %. Found: C 50.28; H 3.62; N 7.80 %.
General procedure for the synthesis of imidazoles 10 and 13.
An amount of 2 mmol of compounds 3, 6 was dissolved in the solution of glacial acetic acid (5 mL) and HCl (1 mL), and KSCN (0.78 g, 8 mmol) was added. The reaction mixture was heated at reflux for 4 h, then it was cooled down, diluted with water, and the precipitate was filtered off and washed with water and n-hexane.
3-(4-(4-bromophenyl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)benzenesulfonamide (10). Yellowish solid, yield 0.59 g (72%); m.p. 280–281 °C; IR (KBr) (v, cm−1): 3258, 2729, 1485; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.52 (s, 2H, NH2), 7.60–7.79 (m, 5H, Har), 7.84–7.98 (m, 2H, Har), 8.02 (s, 1H, Har), 8.18 (s, 1H, CH), 13.12 (s, 1H, SH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 116.38, 120.95, 122.98, 125.01, 126.26, 126.86, 127.65, 129.25, 129.68, 131.81, 137.79, 144.76, 163.17; Anal. Calcd. For C15H12BrN3O2S2: C 43.91; H 2.95; N 10.24 %. Found: C 43.99; H 2.91; N 10.21 %.
3-(2-thioxo-4-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazol-1-yl)benzenesulfonamide (13). Light brown solid, yield 0.51 g (75%); m.p. 226–227 °C; IR (KBr) (v, cm−1): 3141, 2737, 1489; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.53 (s, 2H, NH2), 7.72–8.05 (m, 7H, Har), 8.13–8.24 (m, 2H, CH, Har), 13.26 (s, 1H, SH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 117.77, 123.06, 124.75, 125.14, 125.91, 125.95, 127.24, 127.67, 127.99, 129.32, 129.71, 131.53, 137.70, 144.80, 163.62; Anal. Calcd. For C16H12F3N3O2S2: C 48.12; H 3.03; N 10.52; %. Found: C 48.10; H 2.99; N 10.47 %.
General procedure for the synthesis of S-alkylated compounds 16–22a-c.
Imidazole 9–15 (1.0 mmol) was dissolved in DMF (3 mL). Triethylamine (0.5 mL) and corresponding alkyl halide (1.5 mmol) were added dropwise, and the reaction mixture was stirred at room temperature for 2–3 h. Then, the reaction mixture was diluted with 20 mL of water. The precipitate was filtered off, washed with water and diethyl ether, dried, and recrystallized from propan-2-ol.
3-(2-(methylthio)-4-phenyl-1H-imidazol-1-yl)benzenesulfonamide (16a). White solid, yield 0.29 g (84%); m.p. 148–149 °C; IR (KBr) (v, cm−1): 3327, 1483; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.63 (s, 3H, CH3), 7.25 (t, 1H, J = 7.4 Hz, Har), 7.23 (t, 2H, J = 7.6 Hz, Har), 7.57 (br. S, 2H, NH2), 7.75–7.98 (m, 6H, Har), 8.08 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 14.83, 27.56, 115.34, 115.56, 118.69, 122.32, 125.44, 126.21, 126.29, 128.63, 130.00, 130.03, 130.47, 136.94, 140.57, 141.88, 145.36; Anal. Calcd. For C16H15N3O3S2: C 55.63; H 4.38; N 12.16; %. Found: C 55.57; H 4.35; N 12.13 %.
3-(2-(ethylthio)-4-phenyl-1H-imidazol-1-yl)benzenesulfonamide (16b). Light yellow solid, yield 0.27 g (75%); m.p. 160–161 °C; IR (KBr) (v, cm−1): 3324, 1482; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 (t, 3H, J = 7.3 Hz, CH3), 3.14 (q, 2H, J = 7.3 Hz, CH2), 7.23 (t, 2H, J = 8.7 Hz, Har), 7.57 (br. S, 2H, NH2), 7.70–8.00 (m, 6H, Har), 8.08 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 14.84, 27.59, 118.84, 122.34, 124.38, 125.40, 126.87, 128.59, 128.64, 130.46, 133.43, 136.99, 141.46, 141.79, 145.35; Anal. Calcd. For C17H17N3O2S2: C 56.80; H 4.77; N 11.69; %. Found: C 56,79; H 4.75; N 11.64 %.
3-(4-phenyl-2-(propylthio)-1H-imidazol-1-yl)benzenesulfonamide (16c). White solid, yield 0.30 g (81%); m.p. 130–131 °C; IR (KBr) (v, cm−1): 3332, 1483; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.92 (t, 3H, J = 7.3 Hz, CH3), 1.67 (extette, 2H, J = 7.3 Hz, CH2), 3.12 (t, 2H, J = 7.1 Hz, SCH2), 7.25 (t, 1H, J = 7.4 Hz, Har), 7.40 (t, 2H, J = 7.6 Hz, Har), 7.57 (br. S, 2H, NH2), 7.73–7.87 (m, 4H, Har), 7.94 (br. S, 2H, Har), 8.08 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 13.04, 22.41, 35.18, 118.85, 122.36, 124.36, 125.40, 126.86, 128.58, 128.65, 130.45, 133.43, 137.00, 141.40, 141.92, 145.36; Anal. Calcd. For C18H19N3O2S2: C 57.89; H 5.13; N 11.25; %. Found: C 57.88; H 5.09; N 11.29 %.
3-(4-(4-bromophenyl)-2-(methylthio)-1H-imidazol-1-yl)benzenesulfonamide (17a). White solid, yield 0.36 g (85%); m.p. 168–169 °C; IR (KBr) (v, cm−1): 3351, 1480; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.63 (s, 3H, CH3), 7.54–7.62 (m, 4H, NH2, Har), 7.76–7.84 (m, 4H, Har), 7.94 (br. S, 2H, Har), 8.16 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 15.44, 119.39, 119.60, 122.11, 125.52, 126.32, 128.42, 130.58, 131.50, 132.70, 136.77, 140.23, 143.35, 145.45; Anal. Calcd. For C16H14BrN3O2S2: C 45.29; H 3.33; N 9.90; %. Found: C 45.25; H 3.29; N 9.90 %.
3-(4-(4-bromophenyl)-2-(ethylthio)-1H-imidazol-1-yl)benzenesulfonamide (17b). White solid, yield 0.38 g (80%); m.p. 142–143 °C; IR (KBr) (v, cm−1): 3350, 1479; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 (t, 3H, J = 7.3 Hz, CH3), 3.15 (q, 2H, J = 7.3 Hz, CH2), 7.53–7.61 (m, 4H, NH2, Har), 7.73–7.83 (m, 4H, Har), 7.90–7.96 (m, 2H, Har), 8.16 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 14.82, 27.50, 119.42, 119.63, 122.32, 125.50, 126.34, 128.64, 130.49, 131.52, 132.72, 136.86, 140.31, 142.20, 145.35; Anal. Calcd. For C17H16BrN3O2S2: C 46.58; H 3.68; N 9.59; %. Found: C 46.61; H 3.69; N 9.55 %.
3-(4-(4-bromophenyl)-2-(propylthio)-1H-imidazol-1-yl)benzenesulfonamide (17c). White solid, yield 0.39 g (75%); m.p. 163–164 °C; IR (KBr) (v, cm−1): 3352, 1479; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.92 (t, 3H, J = 7.3 Hz, CH3), 1.66 (extette, 2H, J = 7.2 Hz, CH2), 3.13 (t, 2H, J = 7.1 Hz, SCH2), 7.52–7.63 (m, 4H, NH2, Har), 7.73–7.84 (m, 4H, Har), 7.89–7.96 (m, 2H, Har), 8.15 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 13.04, 22.37, 35.10, 119.42, 119.63, 122.35, 125.50, 126.32, 128.65, 130.48, 131.52, 132.71, 136.87, 140.25, 142.34, 145.38; Anal. Calcd. For C18H18BrN3O2S2: C 47.79; H 4.01; N 9.29; %. Found: C 47.76; H 3.98; N 9.25 %.
3-(4-(4-chlorophenyl)-2-(methylthio)-1H-imidazol-1-yl)benzenesulfonamide (18a). Brownish solid, yield 0.28 g (74%); m.p. 171–172 °C; IR (KBr) (v, cm−1): 3347, 1482; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.63 (s, 3H, CH3), 7.45 (d, 2H, J = 8.2 Hz, Har), 7.57 (br. S, 2H, NH2), 7.74–7.90 (m, 4H, Har), 7.95 (br. S, 2H, Har), 8.14 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 15.45, 119.33, 122.12, 125.52, 126.00, 128.42, 128.61, 130.59, 131.12, 132.35, 136.79, 140.22, 143.33, 145.46; Anal. Calcd. For C16H14ClN3O2S2: C 50.59; H 3.71; N 11.06; %. Found: C 50.58; H 3.68; N 11.01 %.
3-(4-(4-chlorophenyl)-2-(propylthio)-1H-imidazol-1-yl)benzenesulfonamide (18c). Light brown solid, yield 0.35 g (85%); m.p. 166–167 °C; IR (KBr) (v, cm−1): 3348, 1481; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.93 (t, 3H, J = 7.3 Hz, CH3), 1.67 (sextet, 2H, J = 7.3 Hz, CH2), 3.13 (t, 2H, J = 7.1 Hz, SCH2), 7.46 (d, 2H, J = 8.3 Hz, Har), 7.58 (br. S, 2H, NH2), 7.74–7.99 (m, 6H, Har), 8.15 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 13.04, 22.38, 35.10, 119.37, 122.35, 125.50, 126.00, 128.62, 128.65, 130.48, 131.13, 132.36, 136.88, 140.23, 142.31, 145.38; Anal. Calcd. For C18H18ClN3O2S2: C 53.00; H 4.45; N 10.30; %. Found: C 52.99; H 4.39; N 10.30 %.
3-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-1-yl)benzenesulfonamide (19a). Yellowish solid, yield 0.29 g (81%); m.p. 162–163 °C; IR (KBr) (v, cm−1): 3341, 1484; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.63 (s, 3H, CH3), 7.23 (t, 2H, J = 8.7 Hz, Har), 7.57 (br. S, 2H, NH2), 7.75–7.98 (m, 6H, Har), 8.08 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 15.50, 115.33, 115.55, 118.64, 122.10, 125.45, 126.20, 126.28, 128.40, 130.00, 130.03, 130.57, 136.86, 140.51, 143.04, 145.45; Anal. Calcd. For C16H14FN3O2S2: C 52.88; H 3.88; N 11.56; %. Found: C 52.85; H 3.89; N 11.51 %.
3-(2-(ethylthio)-4-(4-fluorophenyl)-1H-imidazol-1-yl)benzenesulfonamide (19b). Yellowish solid, yield 0.31 g (82%); m.p. 160–161 °C; IR (KBr) (v, cm−1): 3350, 1483; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 (t, 3H, J = 7.3 Hz, CH3), 3.14 (q, 2H, J = 7.3 Hz, CH2), 7.24 (t, 2H, J = 8.7 Hz, Har), 7.57 (br. S, 2H, NH2), 7.69–7.99 (m, 6H, Har), 8.09 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 14.84, 27.59, 115.36, 115.57, 118.72, 122.33, 125.46, 126.22, 126.30, 128.64, 129.97, 130.48, 136.92, 140.51, 141.88, 145.37; Anal. Calcd. For C17H16FN3O2S2: C 54.10; H 4.27; N 11.13; %. Found: C 54.05; H 4.23; N 11.09 %.
3-(4-(4-fluorophenyl)-2-(propylthio)-1H-imidazol-1-yl)benzenesulfonamide (19c). White solid, yield 0.30 g (77%); m.p. 142–143 °C; IR (KBr) (v, cm−1): 3350, 1484; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.92 (t, 3H, J = 7.3 Hz, CH3), 1.66 (sextet, 2H, J = 7.2 Hz, CH2), 3.12 (t, 2H, J = 7.1 Hz, SCH2), 7.23 (t, 2H, J = 8.6 Hz, Har), 7.57 (br. S, 2H, NH2), 7.72–7.96 (m, 6H, Har), 8.07 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 13.04, 22.40, 35.15, 115.35, 115.56, 118.70, 122.33, 125.43, 126.19, 126.27, 128.64, 130.00, 130.03, 130.47, 136.95, 140.51, 142.01, 145.36; Anal. Calcd. For C18H18FN3O2S2: C 55.23; H 4.63; N 10.73; %. Found: C 55.19; H 4.57; N 10.76 %.
3-(2-(methylthio)-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)benzenesulfonamide (20a). Yellow solid, yield 0.34 g (83%); m.p. 206–207 °C; IR (KBr) (v, cm−1): 3341, 1484; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.65 (s, 3H, CH3), 7.58 (br. S, 2H, NH2), 7.71–7.84 (m, 4H, Har), 7.91–8.12 (m, 4H, Har), 8.30 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 15.41, 120.65, 122.18, 123.11, 124.70, 125.53, 125.57, 125.61, 125.66, 125.81, 126.72, 127.03, 128.48, 130.62, 136.68, 137.39, 139.87, 143.88, 145.50; Anal. Calcd. For C17H14F3N3O2S2: C 49.39; H 3.41; N 10.16; %. Found: C 49.31; H 3,43; N 10.11 %.
3-(2-(ethylthio)-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)benzenesulfonamide (20b). White solid, yield 0.33 g (77%); m.p. 154–155 °C; IR (KBr) (v, cm−1): 3334, 1483; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.32 (t, 3H, J = 7.3 Hz, CH3), 3.17 (q, 2H, J = 7.3 Hz, CH2), 7.58 (br. S, 2H, NH2), 7.70–7.85 (m, 4H, Har), 7.95 (br. S, 2H, Har), 8.05 (d, 2H, J = 8.1 Hz, Har), 8.30 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 14.80, 27.49, 120.65, 122.39, 123.10, 124.73, 125.55, 125.59, 125.64, 125.81, 126.75, 127.07, 128.69, 130.53, 136.77, 137.42, 139.95, 142.74, 145.42; Anal. Calcd. For C18H16F3N3O2S2: C 50.58; H 3.77; N 9.83; %. Found: C 50.55; H 3.72; N 9.79 %.
3-(2-(propylthio)-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)benzenesulfonamide (20c). Yellowish solid, yield 0.38 g (86%); m.p. 133–134 °C; IR (KBr) (v, cm−1): 3352, 1486; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.93 (t, 3H, J = 7.3 Hz, CH3), 1.68 (sextet, 2H, J = 7.3 Hz, CH2), 3.15 (t, 2H, J = 7.1 Hz, SCH2), 7.58 (br. S, 2H, NH2), 7.70–7.84 (m, 4H, Har), 7.95 (br. S, 2H, Har), 8.05 (d, 2H, J = 8.1 Hz, Har), 8.29 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 13.04, 22.36, 35.08, 120.66, 122.41, 123.10, 124.71, 125.55, 125.59, 125.64, 125.80, 126.75, 127.06, 128.71, 130.52, 136.78, 137.41, 139.89, 142.87, 145.43; Anal. Calcd. For C19H18F3N3O2S2: C 51.69; H 4.11; N 9.52; %. Found: C 51.63; H 4.09; N 9.50 %.
3-(4-(4-cyanophenyl)-2-(methylthio)-1H-imidazol-1-yl)benzenesulfonamide (21a). Light yellow solid, yield 0.26 g (70%); m.p. 192–193 °C; IR (KBr) (v, cm−1): 3336, 1484; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.65 (s, 3H, CH3), 7.58 (br. S, 2H, NH2), 7.77–7.89 (m, 4H, Har), 7.93–8.05 (m, 4H, Har), 8.34 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 15.36, 108.76, 119.15, 121.37, 122.19, 124.77, 125.74, 128.50, 130.65, 132.70, 136.59, 137.93, 139.63, 144.22, 145.51; Anal. Calcd. For C17H14N4O2S2: C 55.12; H 3.81; N 15.12; %. Found: C 55.07; H 3.78; N 15.13 %.
3-(4-(4-cyanophenyl)-2-(ethylthio)-1H-imidazol-1-yl)benzenesulfonamide (21b). Light yellow solid, yield 0.29 g (76%); m.p. 204–205 °C; IR (KBr) (v, cm−1): 3350, 1483; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.32 (t, 3H, J = 7.3 Hz, CH3), 3.17 (q, 2H, J = 7.3 Hz, CH2), 7.58 (br. S, 2H, NH2), 7.74–8.09 (m, 8H, Har), 8.34 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 14.80, 27.44, 108.78, 119.15, 121.37, 122.38, 124.78, 125.72, 128.71, 130.57, 132.72, 136.67, 137.95, 139.69, 143.09, 145.44; Anal. Calcd. For C18H16N4O2S2: C 56.23; H 4.19; N 14.57; %. Found: C 56.17; H 4.15; N 14.59 %.
3-(4-(4-cyanophenyl)-2-(propylthio)-1H-imidazol-1-yl)benzenesulfonamide (21c). White solid, yield 0.27 g (68%); m.p. 210–211 °C; IR (KBr) (v, cm−1): 3351, 1483; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.93 (t, 3H, J = 7.3 Hz, CH3), 1.68 (sextet, 2H, J = 7.2 Hz, CH2), 3.15 (t, 2H, J = 7.1 Hz, SCH2), 7.58 (br. S, 2H, NH2), 7.75–8.07 (m, 8H, Har), 8.33 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 13.05, 22.37, 35.01, 108.78, 119.15, 121.37, 122.40, 124.77, 125.73, 128.71, 130.56, 132.72, 136.68, 137.94, 139.64, 143.23, 145.44; Anal. Calcd. For C19H18N4O2S2: C 57.27; H 4.55; N 14.06; %. Found: C 57.21; H 4.50; N 14.08 %.
3-(2-(methylthio)-4-(4-nitrophenyl)-1H-imidazol-1-yl)benzenesulfonamide (22a). Yellow solid, yield 0.31 g (79%); m.p. 204–205 °C; IR (KBr) (v, cm−1): 3264, 1489; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.66 (s, 3H, CH3), 7.58 (br. S, 2H, NH2), 7.78–7.84 (m, 2H, Har), 7.97 (br. S, 2H, Har), 8.09 (d, 2H, J = 8.4 Hz, Har), 8.28 (d, 2H, J = 8.4 Hz, Har), 8.42 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 15.34, 122.12, 122.19, 124.23, 124.85, 125.81, 128.51, 130.67, 136.51, 139.30, 140.00, 144.63, 145.52, 145.71; Anal. Calcd. For C16H14N4O2S2: C 49.22; H 3.61; N 14.35; %. Found: C 49.24; H 3.57; N 14.37 %.
3-(2-(ethylthio)-4-(4-nitrophenyl)-1H-imidazol-1-yl)benzenesulfonamide (22b). Yellow solid, yield 0.33 g (81%); m.p. 188–189 °C; IR (KBr) (v, cm−1): 3312, 1484; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.33 (t, 3H, J = 7.3 Hz, CH3), 3.19 (q, 2H, J = 7.3 Hz, CH2), 7.59 (br. S, 2H, NH2), 7.74–7.86 (m, 2H, Har), 7.96 (br. S, 2H, Har), 8.09 (d, 2H, J = 8.5 Hz, Har), 8.27 (d, 2H, J = 8.5 Hz, Har), 8.42 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 14.78, 27.43, 122.08, 122.38, 124.23, 124.87, 125.79, 128.70, 130.58, 136.60, 139.37, 140.01, 143.50, 145.46, 145.73; Anal. Calcd. For C17H16N4O2S2: C 50.48; H 3.99; N 13.85; %. Found: C 50.49; H 3.99; N 13.79 %.
3-(4-(4-nitrophenyl)-2-(propylthio)-1H-imidazol-1-yl)benzenesulfonamide (22c). Yellow solid, yield 0.34 g (81%); m.p. 174–175 °C; IR (KBr) (v, cm−1): 3314, 1484; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.94 (t, 3H, J = 7.3 Hz, CH3), 1.69 (sextet, 2H, J = 7.3 Hz, CH2), 3.17 (t, 2H, J = 7.1 Hz, SCH2), 7.58 (br. S, 2H, NH2), 7.76–7.85 (m, 2H, Har), 7.96 (br. S, 2H, Har), 8.08 (d, 2H, J = 8.5 Hz, Har), 8.28 (d, 2H, J = 8.5 Hz, Har), 8.41 (s, 1H, CH); 13C NMR (101 MHz, DMSO-d6) (δ, ppm): 13.06, 22.33, 35.00, 122.12, 122.40, 124.24, 124.86, 125.79, 128.73, 130.58, 136.61, 139.31, 140.00, 143.62, 145.45, 145.73; Anal. Calcd. For C18H18N4O2S2: C 51.66; H 4.34; N 13.39; %. Found: C 51.62; H 4.29; N 13.37 %.

2.3. Minimal Inhibitory Concentration Determination

2.3.1. Preparation of Assay Microplates

The minimal inhibitory concentrations (MICs) of compounds 2–22a–c, as well as of clinically approved antibiotics (rifampin, isoniazid, amikacin, levofloxacin, and meropenem) were determined by microplate broth dilution method as described by Clinical Laboratory Standards Institute document M07-A8. The antimicrobials were selected to represent major antimicrobials used in clinical settings to treat MDR infections, as well as infections caused by rapidly growing Mycobacterium spp. The MICs for the compounds and comparator antibiotics were determined against the libraries of Gram-positive and Gram-negative pathogens, multidrug-resistant fungi, and mycobacteria.
Compounds and antibiotics that were used as a control were dissolved in molecular biology grade dimethyl sulfoxide (DMSO) to achieve a final concentration of 25–30 mg/mL. Compound dilutions were achieved in 1.5 mL polypropylene 96-well microplates to generate 2× of concentrations of each drug (0.5–64 µg/mL). The 2× concentrates were then then transferred to flat bottom plates and used for inoculation or stored in argon purged sealed bags at −80 °C.

2.3.2. Antibacterial Activity Characterization Using Gram-Positive and Gram-Negative Pathogens

A microbial inoculum was prepared using the direct colony suspension method and densitometric analysis. The inoculum suspension of each test organism was prepared in 5 mL of sterile deionized water until densitometer reached 0.5 MFa and further diluted in sterile CAMBH media to achieve final concentrations of approximately 5 × 105 CFU/mL in each well after dispensing in microplates. The inoculum was transferred to the assay plates to achieve 1× assay concentration. A 10 µL of inoculum was plated on Sheep Blood agar plates to validate the purity and inoculum size. Inoculated microdilution plates were incubated at 35 °C for 16 to 20 h in an ambient-air incubator.

2.3.3. Antifungal Activity Characterization

The MIC of compounds 2–22a–c, as well as clinically approved antifungal drugs was determined by CLSI recommendations that were described in document M27-A3 [36,37]. Multidrug-resistant Candida spp. strains were sub-cultured on Sabouraud-Dextrose agar for 24 h at 35 °C. Drug-resistant Aspergillus fumigatus was cultured on Inhibitory mold agar slants for 5 days at 35 °C. The colonies of Candida isolates were suspended in sterile saline to reach approximately 5 × 106 CFU/mL. The conidia of A. fumigatus were collected by flooding the slants with saline containing 0.5% of Tween 80 and passing conidia through 75 µm cell strainer. The inoculums were quantified by using haematocytometer and then, the fungal suspension was diluted in RPMI/MOPS broth to reach 5 × 105 CFU/mL. The inoculum was then dispensed in assay microplates, and inoculated microdilution plates were incubated at 35 °C for 24 h in an ambient-air incubator within 15 min of the addition of the inoculum.

2.3.4. Antimycobacterial Activity Determination

Before the experiments, multidrug-resistant M. abscessus complex strains were cultured on Middlebrook 7H9 agar containing ODAC supplement for four days at 37 °C. M. bovis BCG and avirulent M. tuberculosis H37Ra strains were grown on Lowenstein–Jensen (LJ) media for 3 weeks.
The colonies of M. abscessus were scraped and suspended in tube with sterile saline to achieve approximately 5 × 106 CFU/mL. M. bovis BCG and M. tuberculosis H37Ra were scraped from the LJ media and transferred to the tube containing 4 mL of Middlebrook 7H9 broth and 3 borosilicate glass beads. The tube was vortexed on maximum speed for 2 min, and then, the bacterial suspension was adjusted to 5 × 106 CFU/mL. Prior to inoculation of the plates, the bacterial suspension was diluted 1:10 in Middlebrook 7H9 broth containing 20 µg/mL of resazurin, and microplates were inoculated by using multichannel pipette.
The plates were incubated at 37 °C in humidified incubator for 5 days (for M. abscessus complex) or two weeks (for M. bovis BCG and M. tuberculosis H37Ra) and the minimal inhibitory concentration was determined by visual evaluation.

3. Results and Discussion

3.1. Chemistry

Most of the compounds 2–15 (Scheme 1) were resynthesized according to our previous study [35] and were further investigated during this study. All the spectral data and reaction conditions can be found in previously mentioned research [35]. Moreover, to explore further on benzenesulfonamide-bearing 1H-imidazolethiol moieties, new compounds 3, 6, 10, and 13 were newly synthesized for this study (Scheme 1). 3-Aminobenzenesulfonamide (1) was treated with various α-halogenketones in water/1,4-dioxane solution to afford compound 3 and 6. These intermediate compounds were later cyclized with potassium thiocyanate in glacial acetic acid and in a presence of HCl as a catalyst into 1H-imidazole derivatives 10 and 13. The structures of compounds 3, 6, 10, and 13 have also been confirmed by the data of FT-IR, 1H and 13C NMR spectroscopy, as well as elemental analysis data. For instance, in a 1H NMR spectrum for 10, the singlets assigned to the protons in the CH group at 8.18 ppm and in the SH group at 13.12 ppm have proven the presence of 1H-imidazolethiol moiety in the molecule. One of the best-known properties of thioamides is the tautomerism [38]: thioamides can exist in their thione/thiol forms. However, the 13C NMR spectral data showed that in DMSO-d6 solvent, thiol tautomeric form is predominant for both compounds 10 and 13. The carbon attributed to the C-SH group resonated at 163.17 and 163.62 ppm, respectively.
The main goal of this study was to further investigate 1H-imidazolethiol derivatives with various alkyl substituents. For this purpose, S-alkylation reactions with bromomethane, ethyl iodide, and n-propyl iodide in dimethyl formamide were carried out to obtain compounds 16–22a–c. Triethylamine was used as a base catalyst to increase the reaction rate. For example, in a 1H NMR spectrum for 16a, the singlet assigned to the protons in the CH3 group at 2.63 ppm have proved the presence of methyl moiety in the molecule, while a triplet at 0.92 ppm, a sextet at 1.67 ppm, and a triplet at 3.12 ppm assigned to the protons in the CH3, CH2, and CH3, respectively, proved the presence of a propyl group in compound 16c. Elemental analysis data of compounds 16–22a–c confirmed that all the molecules did not form hydroiodide or hydrobromide salts.

3.2. Benzenesulfonamide Derivatives 2-22a-c Demonstrated Structure-Depended Antimicrobial Activity against Multidrug-Resistant Non-Tuberculous Mycobacteria

Novel benzenesulfonamide derivatives bearing substituted imidazoles demonstrated structure-depended antimicrobial activity against Mycobacterium abscessus complex strains (Table 1). Notably, compounds 2–22a–c showed little activity against multidrug-resistant Gram-positive and Gram-negative bacterial strains or drug-resistant fungi, suggesting the mycobacteria-directed activity (Tables S1 and S2).
Compounds 2–5, bearing 4-H or halogen substitutions demonstrated no antimicrobial activity against M. abscessus complex strains, as well as M. bovis BCG or M. tuberculosis H37Ra (MIC > 64 µg/mL). The addition of the 4-CF3 substitution on the benzenesulfonamide core in compound 6 resulted in weak antimicrobial activity against M. abscessus complex strains (MIC 64 µg/mL) except for M. abscessus MA1836. Moreover, compound 7 showed no activity against M. bovis BCG or M. tuberculosis H37Ra strains (MIC > 64 µg/mL). Furthermore, the incorporation of 4-CN (7), or 4-NO2 (8), in the benzenesulfonamide nucleus diminished the antimicrobial activity against M. abscessus complex, as well as M. bovis BCG or M. tuberculosis H37Ra (Table 1).
The incorporation of imidazole-2-thiol moiety in compound 9 resulted in weak antimicrobial activity against M. abscessus complex strains (MIC 64 µg/mL) with exception of M. abscessus MA1704 and MA0040 (MIC > 64 µg/mL). The incorporation of imidazole-2-thiol moiety (compound 9) resulted in extended antimicrobial activity against rapidly growing M. abscessus strains, non-tuberculous mycobacteria (M. bovis BCG), as well as M. tuberculosis H37Ra (MIC 32 µg/mL, respectively). Interestingly, 4-Br, 4-Cl substitutions in imidazole-2-thiol derivatives (10,11) resulted in loss of antimicrobial activity against mycobacteria, while 4-F substitution (12) resulted in antimicrobial activity against M. abscessus complex (MIC 32–64 µg/mL) and loss of activity against M. bovis BCG and M. tuberculosis H37Ra (MIC > 64 µg/mL). The further addition of 4-CF3 substitution resulted in compound 13 with strong antimicrobial activity against tested mycobacterial strains (MIC 0.5–4µ g/mL). The antimicrobial activity of compound 13 against M. abscessus complex was greater than rifampicin (MIC 32–64 µg/mL), isoniazid (MIC 4–32 µg/mL), amikacin (MIC 16–32 µg/mL), levofloxacin (MIC 8–32 µg/mL), and meropenem (MIC 8–64 µg/mL) (Table 1).
The incorporation of an aryl group often results in increased lipophilicity of the compounds. Therefore, we further postulated that the incorporation of various length aryl substitutions if benzenesulfonamide derivatives could enhance the mycobacteria-directed antimicrobial activity. Compound 16a bearing methyl group demonstrated weak antimicrobial activity against M. abscessus complex strains MA1884 and MA1753 (MIC 64 µg/mL). The elongation of the aryl chain by adding ethyl and propyl groups (16b and 16c) diminished the antimicrobial activity. On the other hand, compounds 18a–c containing the 4-Cl substitution demonstrated that the length of the aryl chain is mediating the antimicrobial activity. Compound 18a bearing the methyl substitution showed no antimicrobial activity while compound 18b containing the ethyl group showed antimicrobial activity against M. abscessus complex (MIC 32–64 µg/mL), but not M. bovis BCG or M. tuberculosis H37Ra (MIC > 64 µg/mL). Notably, the incorporation of propyl substitution (18c) resulted in enhanced antimicrobial activity against all tested M. abscessus complex strains (MIC 16–64 µg/mL), as well as M. bovis BCG (MIC 32 µg/mL) and M. tuberculosis H37Ra (MIC 16 µg/mL). Furthermore, compound bearing 4-F substituent and methyl group (19a) showed good antimicrobial activity against M. abscessus complex strains, as well as M. bovis BCG and M. tuberculosis H37Ra (MIC 4–8 µg/mL respectively). However, other S-alkyl groups–ethyl (19b) and propyl (19c) in imidazole bearing 4-fluorophenyl substituent completely diminished antimicrobial activity against tested strains (Table 1).

4. Conclusions

During this study, a series of imidazole-2-thiol bearing benzenesulfonamides was synthesized. To reach higher lipophilicity properties and potentially increase their membrane permeability through multidrug-resistant mycobacteria, various S-alkylation reactions were performed with alkyl halides.
Synthesized compounds showed structure-dependent antimicrobial activity against Mycobacterium abscessus complex strains. Furthermore, compounds 2–22a–c showed little activity against multidrug-resistant Gram-positive and Gram-negative bacterial strains or drug-resistant fungi. However, 3-(2-thioxo-4-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazol-1-yl)benzenesulfonamide (13) has demonstrated high antibacterial activity against all tested mycobacterial strains and was more active than widely used antibiotics like rifampin, amikacin, or levofloxacin.
Previous studies have explored the impact of alkyl substitution on the antimicrobial activity of various compounds against mycobacteria and other clinically important pathogens. Oh et al. [39] have reported the synthesis of a series of novel N-Alkyl-5-hydroxypyrimidinone carboxamides as potent inhibitors of M. tuberculosis decaprenylphosphoryl-β-d-ribose 2’-oxidase. Faria et al. [40] describes alkyl promising activity and the high reactivity of alkyl hydrazide derivatives of isoniazid, suggesting that the alkylation is an important modification leading to the in vitro and in silico activity. Yang Yong et al. [41] described the synthesis of novel 8-alkylberberine derivatives bearing aliphatic chains and evaluated their antimicrobial activity. The study showed that increasing the length of the aliphatic chain had a significant effect on the antibacterial activity of the compounds. However, antimicrobial activity started to decrease when alkyl chain consisted eight or more carbon atoms.
S-alkylation is widely employed strategy to increase the stability of biologically active compounds due to higher bond dissociation energy of the S-C bond compared to the N-C bond [42,43]. S-alkylated compounds are generally less susceptible to hydrolysis and more resistant to metabolic degradation compared to N-alkylated compounds, making S-alkylation an attractive strategy to enhance the biological activity of various compounds.
In our study, we compared S-alkylated benzenesulfonamide bearing imidazole derivatives against multidrug-resistant M. abscesus complex strains, and we found that 3-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-1-yl)benzenesulfonamide (19a) and 3-(4-(4-chlorophenyl)-2-(propylthio)-1H-imidazol-1-yl)benzenesulfonamide 18c showed the highest antimycobacterial activity. For instance, MICs of compound 19a with 4-fluorophenyl and S-methyl substituents against M. abscessus complex strains, as well as M. bovis BCG and M. tuberculosis H37Ra, were 4–8 µg/mL, respectively. However, ethyl or propyl groups in the same 1H-imidazol-2-thiol scaffold with 4-fluorophenyl group (compounds 19b and 19c) reduced the potency significantly. As for the imidazole scaffold with 4-chlorophenyl substituent, antimicrobial activity was increased by extending the alkyl chain. Compound 18c containing S-propyl group was more potent than 18a (S-methyl) and 18b (S-ethyl) compounds.
These results suggest that the S-alkylated benzenesulfonamide-bearing imidazole derivatives could be further explored as a scaffold for the development of novel, multidrug-resistant M. abscesus complex-directed antimicrobials.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/microorganisms11040935/s1, Figure S1: 1H NMR of compound 3 at 400 MHz (DMSO-d6), Figure S2: 13C NMR of compound 3 at 101 MHz (DMSO-d6), Figure S3: 1H NMR of compound 6 at 400 MHz (DMSO-d6), Figure S4: 13C NMR of compound 6 at 101 MHz (DMSO-d6), Figure S5: 1H NMR of compound 10 at 400 MHz (DMSO-d6), Figure S6: 13C NMR of compound 10 at 101 MHz (DMSO-d6), Figure S7: 1H NMR of compound 13 at 400 MHz (DMSO-d6), FigureS8: 13C NMR of compound 13 at 101 MHz (DMSO-d6), Figure S9: 1H NMR of compound 16a at 400 MHz (DMSO-d6), Figure S10: 13C NMR of compound 16a at 101 MHz (DMSO-d6), Figure S11: 1H NMR of compound 16b at 400 MHz (DMSO-d6), Figure S12: 13C NMR of compound 16b at 101 MHz (DMSO-d6), Figure S13: 1H NMR of compound 16c at 400 MHz (DMSO-d6), Figure S14: 13C NMR of compound 16c at 101 MHz (DMSO-d6), Figure S15: 1H NMR of compound 17a at 400 MHz (DMSO-d6), Figure S16: 13C NMR of compound 17a at 101 MHz (DMSO-d6), Figure S17: 1H NMR of compound 17b at 400 MHz (DMSO-d6), Figure S18: 13C NMR of compound 17b at 101 MHz (DMSO-d6), Figure S19: 1H NMR of compound 18a at 400 MHz (DMSO-d6), Figure S20: 13C NMR of compound 18a at 101 MHz (DMSO-d6), Figure S21: 1H NMR of compound 18b at 400 MHz (DMSO-d6), Figure S22: 13C NMR of compound 18b at 101 MHz (DMSO-d6), Figure S23: 1H NMR of compound 18c at 400 MHz (DMSO-d6), Figure S24: 13C NMR of compound 18c at 101 MHz (DMSO-d6), Figure S25: 1H NMR of compound 19a at 400 MHz (DMSO-d6), Figure S26: 13C NMR of compound 19a at 101 MHz (DMSO-d6), Figure S27: 1H NMR of compound 19b at 400 MHz (DMSO-d6), Figure S28: 13C NMR of compound 19b at 101 MHz (DMSO-d6), Figure S29: 1H NMR of compound 19c at 400 MHz (DMSO-d6), Figure S30: 13C NMR of compound 19c at 101 MHz (DMSO-d6), Figure S31: 1H NMR of compound 20a at 400 MHz (DMSO-d6), Figure S32: 13C NMR of compound 20a at 101 MHz (DMSO-d6), Figure S33: 1H NMR of compound 20b at 400 MHz (DMSO-d6), Figure S34: 13C NMR of compound 20b at 101 MHz (DMSO-d6), Figure S35: 1H NMR of compound 20c at 400 MHz (DMSO-d6), Figure S36: 13C NMR of compound 20c at 101 MHz (DMSO-d6), Figure S37: 1H NMR of compound 21a at 400 MHz (DMSO-d6), Figure S38: 13C NMR of compound 21a at 101 MHz (DMSO-d6), Figure S39: 1H NMR of compound 21b at 400 MHz (DMSO-d6), Figure S40: 13C NMR of compound 21b at 101 MHz (DMSO-d6), Figure S41: 1H NMR of compound 21c at 400 MHz (DMSO-d6), Figure S42: 13C NMR of compound 21c at 101 MHz (DMSO-d6), Figure S43: 1H NMR of compound 22a at 400 MHz (DMSO-d6), Figure S44: 13C NMR of compound 22a at 101 MHz (DMSO-d6), Figure S45: 1H NMR of compound 22b at 400 MHz (DMSO-d6), Figure S46: 13C NMR of compound 22b at 101 MHz (DMSO-d6), Figure S47: 1H NMR of compound 22c at 400 MHz (DMSO-d6), Figure S48: 13C NMR of compound 22c at 101 MHz (DMSO-d6). Table S1: The in vitro antibacterial activity of compounds 2-22c against multidrug-resistant bacterial strains; Table S2: The in vitro antifungal activity of compounds 2-22c against multidrug-resistant Candida auris strains.

Author Contributions

Conceptualization, V.M. and P.K.; methodology, V.M., B.B. and P.K.; synthesis, B.B.; investigation, B.B., B.G., R.P., V.P., A.G., E.N., R.G. and P.K.; writing—original draft preparation, B.B. and P.K.; writing—review and editing, V.M. and P.K.; supervision, V.M. and P.K. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded by The Doctoral Fund of Kaunas University of Technology No. A-410, approved 26 June 2019, Kaunas, Lithuania.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article and supplementary materials. The compounds are available from the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.

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Microorganisms 11 00935 sch001 550
Scheme 1. Synthesis of compounds (2–22)a–c.
Scheme 1. Synthesis of compounds (2–22)a–c.
Microorganisms 11 00935 sch001
Table
Table 1. The in vitro antimicrobial activity of compounds 2–22a–c against mycobacteria. The minimal inhibitory concentration (MIC) values are provided as an average value obtained from three experimental replicas.
Table 1. The in vitro antimicrobial activity of compounds 2–22a–c against mycobacteria. The minimal inhibitory concentration (MIC) values are provided as an average value obtained from three experimental replicas.
CompoundMinimal Inhibitory Concentration (µg/mL)
M. abscessus MA1884M. abscessus MA1753M. abscessus MA1836M. abscessus MA1704M. abscessus MA0040M. bovis BCGM. tuberculosis H37Ra
2>64>64>64>64>64>64>64
3>64>64>64>64>64>64>64
4>64>64>64>64>64>64>64
5>64>64>64>64>64>64>64
66464>46464>64>64
7>64>64>64>64>64>64>64
8>64>64>64>64>64>64>64
9646464>64>643232
10>64>64>64>64>64>64>64
11>64>64>64>64>64>64>64
1264643264>64>64>64
131444410.5
14>64>64>64>64>64>64>64
15>64>64>64>64>64>64>64
16a6464>64>64>64>64>64
16b>64>64>64>64>64>64>64
16c>64>64>64>64>64>64>64
17a>64>64>64>64>64>64>64
17b>64>64>64>64>64>64>64
17c>64>64>64>64>64>64>64
18a>64>64>64>64>64>64>64
18b6464>64>6432>64>64
18c64643216323216
19a8844844
19b>64>64>64>64>64>64>64
19c>64>64>64>64>64>64>64
20a>64>64>64>64>64>64>64
20b>64>64>64>64>64>64>64
20c>64>64>64>64>64>64>64
21a>64>64>64>64>64>64>64
21b>64>64>64>64>64>64>64
21c>64>64>64>64>64>64>64
22a>64>64>64>64>64>64>64
22b>64>64>64>64>64>64>64
22c6464>64>6464>64>64
Rifampin64>64321632≤0.50.5
Isoniazid841632320.5≤0.5
Amikacin3232161632≤0.5≤0.5
Levofloxacin16816323211
Meropenem8832326484
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Balandis, B.; Kavaliauskas, P.; Grybaitė, B.; Petraitis, V.; Petraitienė, R.; Naing, E.; Garcia, A.; Grigalevičiūtė, R.; Mickevičius, V. Synthesis of Novel Benzenesulfonamide-Bearing Functionalized Imidazole Derivatives as Novel Candidates Targeting Multidrug-Resistant Mycobacterium abscessus Complex. Microorganisms 2023, 11, 935. https://doi.org/10.3390/microorganisms11040935

AMA Style

Balandis B, Kavaliauskas P, Grybaitė B, Petraitis V, Petraitienė R, Naing E, Garcia A, Grigalevičiūtė R, Mickevičius V. Synthesis of Novel Benzenesulfonamide-Bearing Functionalized Imidazole Derivatives as Novel Candidates Targeting Multidrug-Resistant Mycobacterium abscessus Complex. Microorganisms. 2023; 11(4):935. https://doi.org/10.3390/microorganisms11040935

Chicago/Turabian Style

Balandis, Benas, Povilas Kavaliauskas, Birutė Grybaitė, Vidmantas Petraitis, Rūta Petraitienė, Ethan Naing, Andrew Garcia, Ramunė Grigalevičiūtė, and Vytautas Mickevičius. 2023. "Synthesis of Novel Benzenesulfonamide-Bearing Functionalized Imidazole Derivatives as Novel Candidates Targeting Multidrug-Resistant Mycobacterium abscessus Complex" Microorganisms 11, no. 4: 935. https://doi.org/10.3390/microorganisms11040935

APA Style

Balandis, B., Kavaliauskas, P., Grybaitė, B., Petraitis, V., Petraitienė, R., Naing, E., Garcia, A., Grigalevičiūtė, R., & Mickevičius, V. (2023). Synthesis of Novel Benzenesulfonamide-Bearing Functionalized Imidazole Derivatives as Novel Candidates Targeting Multidrug-Resistant Mycobacterium abscessus Complex. Microorganisms, 11(4), 935. https://doi.org/10.3390/microorganisms11040935

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