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

Abstract

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 Mycobacterium tuberculosis 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-N-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 Mycobacterium tuberculosis H37Ra and four other mycobacterial strains (M. aurum, M. smegmatis, M. kansasii, M. avium) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against M. tuberculosis H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, N-(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide (3c, MIC = 3.91 µg/mL or 13.02 µM, SI > 38) and 5-(heptylamino)-N-(p-tolyl)pyrazine-2-carboxamide (4e, 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 Candida genus.

Activity of Semi-Synthetic Mulinanes against MDR, Pre-XDR, and XDR Strains of Mycobacterium tuberculosis

“…Even though the lipophilicity of natural and semi-synthetic derivatives has been reported to be important for favoring their penetration through the lipophilic mycobacterial cell walls [16], no direct correlation was observed between the calculated lipophilicity (logP) and the antimycobacterial activity (Table 1) of the different natural mulinanes and their semi-synthetic derivatives, where the most lipophilic semi-synthetic derivative 1c (logP = 7.34 ± 0.29) proved to be the least active against TB, while the rest of the mulinanes, natural and semi-synthetic, showed similar lipophilicity values but significant differences in their anti-TB activity. While these findings suggest that lipophilicity does not appear to play a significant role in the anti-TB activity of the natural or semisynthetic mulinanes, they do not coincide with results reported in the literature describing that an increase in the lipophilicity of a series of pyridines increased their anti-TB activity [17], and with similar results obtained when evaluating the anti-TB activity of lipophilic derivatives of diphenyland diaryl-pyrroles [18][19][20], and of pentacyclo-undecane-derived cyclic tetraamines [21].…”

Recent Advances in Nanotechnology-Based Strategies for Bone Tuberculosis Management

“…Globally, TB remains a pervasive health challenge, infecting an estimated 2 billion people. While a majority harbor a latent infection, approximately 5–15% develop active symptoms, and 1.4 million people die to this disease every year [ 3 , 4 , 5 ].…”