5-Alkylamino- N -phenylpyrazine-2-carboxamides: Design, Preparation, and Antimycobacterial Evaluation

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-03, Vol.25 (7), p.1561
• Main Authors: Ambrożkiewicz, Weronika, Kučerová-Chlupáčová, Marta, Janďourek, Ondřej, Konečná, Klára, Paterová, Pavla, Bárta, Pavel, Vinšová, Jarmila, Doležal, Martin, Zitko, Jan
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; alkylamino derivatives; antibacterial; Antibacterial activity; antifungal; Antifungal activity; antimycobacterial; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - isolation & purification; Antitubercular Agents - pharmacology; Benzene; Cytotoxicity; Drug Design; Drug Development; Evaluation; Fungicides; HIV; Human immunodeficiency virus; Humans; Hydrocarbons; Infections; Microbial Sensitivity Tests; Minimum inhibitory concentration; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Pyrazinamide; Pyrazinamide - chemistry; Pyrazine; Pyrazines - chemistry; Strains (organisms); Structure-Activity Relationship; Tuberculosis
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25071561

According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by against currently used antituberculars is an imperative to develop new compounds with potential antimycobacterial activity. As a part of our continuous research on structural derivatives of the first-line antitubercular pyrazinamide, we have designed, prepared, and assessed the in vitro whole cell growth inhibition activity of forty-two novel 5-alkylamino- -phenylpyrazine-2-carboxamides with various length of the alkylamino chain (propylamino to octylamino) and various simple substituents on the benzene ring. Final compounds were tested against H37Ra and four other mycobacterial strains ( , , , ) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, -(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide ( , MIC = 3.91 µg/mL or 13.02 µM, SI > 38) and 5-(heptylamino)- -( -tolyl)pyrazine-2-carboxamide ( , MIC = 0.78 µg/mL or 2.39 µM, SI > 20). In a complementary screening, we evaluated the in vitro activity against bacterial and fungal strains of clinical importance. We observed no antibacterial activity and sporadic antifungal activity against the genus.