Synthesis and Antimicrobial Evaluation of 6‐Alkylamino‐N‐phenylpyrazine‐2‐carboxamides

Abstract

This work presents synthesis and antimicrobial evaluation of nineteen 6-alkylamino-N-phenylpyrazine-2-carboxamides. Antimycobacterial activity was determined against Mycobacterium tuberculosis H37Rv, M. kansasii and two strains of M. avium. Generally, the antimycobacterial activity increased with prolongation of simple alkyl chain and culminated in compounds with heptylamino substitution (3e, 4e) with MIC = 5-10 μm against M. tuberculosis H37Rv. On the contrary, derivatives with modified alkyl chain (containing e.g. terminal methoxy or hydroxy group) as well as phenylalkylamino derivatives were mainly inactive. The most active compounds (with hexyl to octylamino substitution) were evaluated for their in vitro activity against drug-resistant strains of M. tuberculosis and possessed activity comparable to that of the reference drug isoniazid. None of the tested compounds were active against M. avium. Some derivatives exhibited activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (best MIC = 7.8 μm), while Gram-negative strains as well as tested fungal strains were completely unsusceptible. Active compounds were tested for in vitro toxicity on various cell lines and in most cases were non-toxic up to 100 μm.

Alkylamino derivatives of N-benzylpyrazine-2-carboxamide: synthesis and antimycobacterial evaluation

“…Our derivatives are sterically more demanding (large substituent on the carboxamide moiety) than the simple amides tested by Simoes et al, 23 therefore their stability (resistance to amidases) is expected to be even higher. According to the results 23 and previously published studies, 12,24 we do not expect that the presented derivatives are hydrolyzed to their corresponding pyrazinecarboxylic acids.…”

Derivatives of 3-Aminopyrazine-2-carboxamides: Synthesis, Antimicrobial Evaluation, and in Vitro Cytotoxicity

“…For alkyl derivatives 9 – 12 , the antimycobacterial and antibacterial activities increase with the increase in the length of the carbon chain. This is in concordance with relationships observed in our previous series of pyrazinamide derivatives [26,27,28,29]. The most active compound against Mtb was compound 17 (phenyl derivative, R’ = 2,4-diOCH 3 ) with MIC = 12.5 µg/mL, 46 µM.…”

“…Based on our experience from the previously published series of alkylamino substituted pyrazinamide derivatives, the antimycobacterial activity was highest for compounds possessing side chains with six to eight carbons [26,27,28,29]. In the alkyl derivatives presented in this paper (compounds 9 – 12 ), octylamide (compound 12 : MIC = 25 µg/mL, 100 µM) exerted the highest activity, followed by heptylamide ( 11 : MIC = 50 µg/mL, 212 µM) and hexylamide ( 10 : MIC = 100 µg/mL, 450 µM).…”

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

“…For antimycobacterial activity, the lipophilicity of a compound is an essential factor since mycobacteria have thick, lipid-rich mycolic cell walls [17]. Besides, chloropyrazine derivatives, specifically anilides of 6-chloropyrazine-2-carboxylic acid, were proven previously to possess in vitro antimycobacterial activity [18,19]. Generally, sulfonamides exert a wide range of biological activities, including anti-tumoral [5], anti-inflammatory [6], anti-convulsant [7], and anti-infective [8], among others.…”