Design and Synthesis of the Linezolid Bioisosteres to Resolve the Serotonergic Toxicity Associated with Linezolid.

Serotonergic toxicity due to MAO enzyme inhibition is a significant concern when using linezolid to treat MDR-TB. To address this issue, we designed linezolid bioisosteres with a modified acetamidomethyl side chain at the C-5 position of the oxazolidine ring to balance activity and reduce toxicity. Among these bioisosteres, R7 emerged as a promising candidate, demonstrating greater effectiveness against M. tuberculosis (Mtb) H37Rv cells with an MIC of 2.01 µM compared to linezolid (MIC = 2.31 µM). Bioisostere R7 also exhibited remarkable activity (MIC50) against drug-resistant Mtb clinical isolates, with values of 0.14 µM (INHR, inhA+), 0.53 µM (INHR, katG+), 0.24 µM (RIFR, rpoB+), and 0.92 µM (INHR INHR, MDR). Importantly, it was >6.52 times less toxic as compared to the linezolid toward the MAO-A and >64 times toward the MAO-B enzyme, signifying a substantial improvement in its drug safety profile.

Repurposing Azoles to Resolve Serotogenic Toxicity Associated with Linezolid to Combat Multidrug-Resistant Tuberculosis.

Serotogenic toxicity is a major hurdle associated with Linezolid in the treatment of drug-resistant tuberculosis (TB) due to the inhibition of monoamine oxidase (MAO) enzymes. Azole compounds demonstrate structural similarities to the recognized anti-TB drug Linezolid, making them intriguing candidates for repurposing. Therefore, we have repurposed azoles (Posaconazole, Itraconazole, Miconazole, and Clotrimazole) for the treatment of drug-resistant TB with the anticipation of their selectivity in sparing the MAO enzyme. The results of repurposing revealed that Clotrimazole showed equipotent activity against the Mycobacterium tuberculosis (Mtb) H37Rv strain compared to Linezolid, with a minimal inhibitory concentration (MIC) of 2.26 µM. Additionally, Clotrimazole exhibited reasonable MIC50 values of 0.17 µM, 1.72 µM, 1.53 µM, and 5.07 µM against the inhA promoter+, katG+, rpoB+, and MDR clinical Mtb isolates, respectively, compared to Linezolid. Clotrimazole also exhibited 3.90-fold less inhibition of MAO-A and 50.35-fold less inhibition of MAO-B compared to Linezolid, suggesting a reduced serotonergic toxicity burden.

Design, Synthesis, and Evaluation of Novel Δ2-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant.

Mycobacterium tuberculosis (Mtb) drug resistance poses an alarming threat to global tuberculosis control. We previously reported that C10, a ring-fused thiazolo-2-pyridone, inhibits Mtb respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant Mtb isolates. This discovery revealed a new strategy to address INH resistance. Expanding upon this strategy, we identified C10 analogues with improved potency and drug-like properties. By exploring three heterocycle spacers (oxadiazole, 1,2,3-triazole, and isoxazole) on the ring-fused thiazolo-2-pyridone scaffold, we identified two novel isoxazoles, 17h and 17j. 17h and 17j inhibited Mtb respiration and biofilm formation more potently with a broader therapeutic window, were better potentiators of INH-mediated inhibition of an INH-resistant Mtb mutant, and more effectively inhibited intracellular Mtb replication than C10. The (-)17j enantiomer showed further enhanced activity compared to its enantiomer and the 17j racemic mixture. Our potent second-generation C10 analogues offer promise for therapeutic development against drug-resistant Mtb.

Usnic Acid Enaminone-Coupled 1,2,3-Triazoles as Antibacterial and Antitubercular Agents.

(+)-Usnic acid, a product of secondary metabolism in lichens, has displayed a broad range of biological properties such as antitumor, antimicrobial, antiviral, anti-inflammatory, and insecticidal activities. Interested by these pharmacological activities and to tap into its potential, we herein present the synthesis and biological evaluation of new usnic acid enaminone-conjugated 1,2,3-triazoles 10-44 as antimycobacterial agents. (+)-Usnic acid was condensed with propargyl amine to give usnic acid enaminone 8 with a terminal ethynyl moiety. It was further reacted with various azides A1-A35 under copper catalysis to give triazoles 10-44 in good yields. Among the synthesized compounds, saccharin derivative 36 proved to be the most active analogue, inhibiting Mycobacterium tuberculosis (Mtb) at an MIC value of 2.5 µM. Analogues 16 and 27, with 3,4-difluorophenacyl and 2-acylnaphthalene units, respectively, inhibited Mtb at MIC values of 5.4 and 5.3 µM, respectively. Among the tested Gram-positive and Gram-negative bacteria, the new derivatives were active on Bacillus subtilis, with compounds 18 [3-(trifluoromethyl)phenacyl] and 29 (N-acylmorpholinyl) showing inhibitory concentrations of 41 and 90.7 µM, respectively, while they were inactive on the other tested bacterial strains. Overall, the study presented here is useful for converting natural (+)-usnic acid into antitubercular and antibacterial agents via incorporation of enaminone and 1,2,3-triazole functionalities.