Substituted N-(Pyrazin-2-yl)benzenesulfonamides; Synthesis, Anti-Infective Evaluation, Cytotoxicity, and In Silico Studies

Abstract

We prepared a series of substituted N-(pyrazin-2-yl)benzenesulfonamides as an attempt to investigate the effect of different linkers connecting pyrazine to benzene cores on antimicrobial activity when compared to our previous compounds of amide or retro-amide linker type. Only two compounds, 4-amino-N-(pyrazin-2-yl)benzenesulfonamide (MIC = 6.25 µg/mL, 25 µM) and 4-amino-N-(6-chloropyrazin-2-yl)benzenesulfonamide (MIC = 6.25 µg/mL, 22 µM) exerted good antitubercular activity against M. tuberculosis H37Rv. However, they were excluded from the comparison as they-unlike the other compounds-possessed the pharmacophore for the inhibition of folate pathway, which was proven by docking studies. We performed target fishing, where we identified matrix metalloproteinase-8 as a promising target for our title compounds that is worth future exploration.Molecules 2020, 25, 138 2 of 20 several compounds containing a pyrazine core directly connected to a sulfonamide moiety-like in our case-are already documented in the literature with a wide range of pharmacological applications [9]. Examples (Figure 2) include zibotentan, an endothelin receptor antagonist with antitumor activity for prostate cancer [10]; halogenated N-(pyrazinyl)benzenesulfonamides, which are clathrin-coated pit (CCP) chemokine receptor antagonists used in treating chemokine mediated diseases (such as asthma) [11]; and sulfamethoxypyrazine (sulfalene), which is an antibacterial sulfonamide agent [12]. As for antitubercular activity of sulfonamides, a fixed combination of sulfamethoxazole [4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide]-trimethoprim [5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine], also known as co-trimoxazole, has in vitro and in vivo antimycobacterial activity against drug-resistant strains of Mycobacterium tuberculosis (Mtb), and it is used for such cases [13,14]. Sulfamethoxazole is a known inhibitor of bacterial dihydropteroate synthase (DHPS), while trimethoprim is an inhibitor of dihydrofolate reductase (DHFR) [15,16]. Molecules 2020, 25, x 2 of 20 Figure 1. Design rationale: general structure of (a) pyrazinecarboxamides = amides; (b) N-pyrazinylbenzamides = retro-amides; and (c) title compounds = sulfonamides.

Reactivity of 4-Bromoacetyl-1,2,3-triazoles towards Amines and Phenols: Synthesis and Antimicrobial Activity of Novel Heterocycles

“…[2][3][4][5] The synthesis of heterocycles containing pyrazine ring systems is therefore of wide interest. [6][7][8][9] The traditional method for the synthesis of pyrazines involves the use of 1,2-diketones in the presence of ammonia to produce the corresponding diamines or aminoketones followed by condensation and oxidation. [10][11][12][13] They can also be produced using -haloor hydroxy-ketones, 14,15 2H-azirines, 16 and nitro epoxides.…”

Synthesis of Novel Sulfamethaoxazole 4-Thiazolidinone Hybrids and Their Biological Evaluation

“…According to the literature survey, it was found that these type of compounds can bind to the matrix metalloproteinase-8 (MMP-8; also known as neutrophil collagenase; PDB ID: 5h8x) [ 47 , 48 ]. This endopeptidase is part of a complex proteolytic MMP enzyme family, where its over expression has been linked to several pathological processes [ 48 ].…”

An overview of sulfonamide‐based conjugates: Recent advances for tuberculosis treatment

“…Moreover, all analogues (1-5) showed inhibitory concentrations of 50% (IC 50 ) and grown inhibitory concentrations of 50% (GI 50 ) >100.0 μg/ml À1 against gram-positive bacteria, gram-negative bacteria, and all analyzed tumor (MCF-7, HCT 116, A549) cell lines (Bhat et al, 2020). Against Mtb (H 37 Rv), Bouz and co-workers (2020) synthetized and assessed the following: Mycobacterium kansasii; Mycobacterium avium; Mycobacterium smeg; and Mycobacterium aurum, a series bearing N-(pyrazin-2-yl) benzenesulfonamide-based analogues (Bouz et al, 2020). Two of these compounds (6-7) presented MIC values of 6.25 μg/ml À1 against Mtb (Figure 3); they (6-7) also showed MIC ranges of 1.56 μg/ml À1 (6) and 12.5 μg/ml À1 (7) against Mycobacterium kansasii, 100.0 μg/ml À1 (6) and 25.0 μg/ml À1 (7) against F I G U R E 3 Novel N-(Pyrazin-2-yl)benzene-based sulfonamide analogues (6-7) (Bouz et al, 2020) (Brown et al, 2019) F I G U R E 5 New Ntrifluoromethylthiolated-based sulfonimidamides/sulfoximines analogues (28-43) (Thota et al, 2019) F I G U R E 6 Novel indazolebased sulfonamide analogues (44-50) (Park et al, 2017) Mycobacterium avium, ≥500.0 μg/ml À1 (6) and ≥ 500.0 μg/ml À1 (7) against Mycobacterium smeg, and 250.0 μg/ml À1 (6) and 250.0 μg/ml À1 (7) against Mycobacterium arum (Bouz et al, 2020).…”

“…Against Mtb (H 37 Rv), Bouz and co-workers (2020) synthetized and assessed the following: Mycobacterium kansasii; Mycobacterium avium; Mycobacterium smeg; and Mycobacterium aurum, a series bearing N-(pyrazin-2-yl) benzenesulfonamide-based analogues (Bouz et al, 2020). Two of these compounds (6-7) presented MIC values of 6.25 μg/ml À1 against Mtb (Figure 3); they (6-7) also showed MIC ranges of 1.56 μg/ml À1 (6) and 12.5 μg/ml À1 (7) against Mycobacterium kansasii, 100.0 μg/ml À1 (6) and 25.0 μg/ml À1 (7) against F I G U R E 3 Novel N-(Pyrazin-2-yl)benzene-based sulfonamide analogues (6-7) (Bouz et al, 2020) (Brown et al, 2019) F I G U R E 5 New Ntrifluoromethylthiolated-based sulfonimidamides/sulfoximines analogues (28-43) (Thota et al, 2019) F I G U R E 6 Novel indazolebased sulfonamide analogues (44-50) (Park et al, 2017) Mycobacterium avium, ≥500.0 μg/ml À1 (6) and ≥ 500.0 μg/ml À1 (7) against Mycobacterium smeg, and 250.0 μg/ml À1 (6) and 250.0 μg/ml À1 (7) against Mycobacterium arum (Bouz et al, 2020). For these compounds, cytotoxicity analysis was performed against hepatocellular carcinoma (HepG2) lines, demonstrating IC 50 values of 775.6 μg/ml À1 (6) and > 500.0 μg/ml À1 (7) (Bouz et al, 2020).…”

“…Two of these compounds (6-7) presented MIC values of 6.25 μg/ml À1 against Mtb (Figure 3); they (6-7) also showed MIC ranges of 1.56 μg/ml À1 (6) and 12.5 μg/ml À1 (7) against Mycobacterium kansasii, 100.0 μg/ml À1 (6) and 25.0 μg/ml À1 (7) against F I G U R E 3 Novel N-(Pyrazin-2-yl)benzene-based sulfonamide analogues (6-7) (Bouz et al, 2020) (Brown et al, 2019) F I G U R E 5 New Ntrifluoromethylthiolated-based sulfonimidamides/sulfoximines analogues (28-43) (Thota et al, 2019) F I G U R E 6 Novel indazolebased sulfonamide analogues (44-50) (Park et al, 2017) Mycobacterium avium, ≥500.0 μg/ml À1 (6) and ≥ 500.0 μg/ml À1 (7) against Mycobacterium smeg, and 250.0 μg/ml À1 (6) and 250.0 μg/ml À1 (7) against Mycobacterium arum (Bouz et al, 2020). For these compounds, cytotoxicity analysis was performed against hepatocellular carcinoma (HepG2) lines, demonstrating IC 50 values of 775.6 μg/ml À1 (6) and > 500.0 μg/ml À1 (7) (Bouz et al, 2020). Brown et al (2019) identified a series of benzoxa-[2,1,3]-diazole amino acid-based sulfonamide derivatives (8-27).…”