In Silico Driven Design and Synthesis of Rhodanine Derivatives as Novel Antibacterials Targeting the Enoyl Reductase...

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Microbiology

Background:

• Mycobacterium tuberculosis (Mtb) remains a significant global health threat.
• InhA, a trans-2-enoyl-acyl carrier protein reductase, is a validated drug target for Mtb.
• Development of novel anti-tubercular agents is crucial to combat drug resistance.

Purpose of the Study:

• To design, synthesize, and evaluate novel 4-thiazolidinone (rhodanine) derivatives as inhibitors of Mtb InhA.
• To assess the antimicrobial and anti-virulence potential of these compounds against various bacterial pathogens.
• To establish structure-activity relationships for optimized anti-tubercular activity.

Main Methods:

• Synthesis of rhodanine derivatives with diverse substituents at positions 5 and N-3.
• In vitro enzymatic assays to determine IC50 values against Mtb InhA.
• Antimicrobial susceptibility testing (MIC determination) against M. marinum, P. aeruginosa, L. pneumophila, and E. faecalis.
• Anti-infective and anti-virulence assays using bacterial models.

Main Results:

• Compounds with bulky aromatic substituents at C5 and a tryptophan at N3 exhibited potent InhA inhibition (IC50: 2.7–30 μM).
• Nineteen of 34 compounds demonstrated anti-virulence activity against M. marinum at 10 μM.
• Compound 33 showed significant antibiotic activity against M. marinum (MIC: 0.21 μM) and reduced L. pneumophila growth (89% at 30 μM).
• Compound 32 displayed potent activity against E. faecalis (MIC: 0.57 μM).

Conclusions:

• Novel rhodanine derivatives effectively inhibit Mtb InhA.
• These compounds possess broad-spectrum antimicrobial and anti-virulence properties.
• The study provides a promising lead for developing new anti-tubercular and anti-infective agents.