Synthesis and Multitarget Activity of Thiadiazole–Thiocoumarin Hybrids: A New Class of Broad-Spectrum Anti-Infective Agents

Abstract

Emerging resistance across infectious pathogens has escalated the demand for chemotherapeutics with multitarget efficacy and minimal cytotoxicity. Herein, we report synthesizing a novel series of thiadiazole–thiocoumarin hybrid derivatives (A1–A10), designed to integrate redox activity with pharmacophoric rigidity. These compounds were evaluated for a spectrum of biological activities, including trypanocidal, antitubercular, antimalarial, antimicrobial, and antioxidant potential. The synthesized hybrids displayed varying degrees of efficacy against Trypanosoma cruzi (NINOA and INC-5 strains), Mycobacterium tuberculosis H37Rv, Plasmodium falciparum, and multiple bacterial and fungal strains. Among the series, compound A9 showed exceptional trypanocidal and antitubercular activity (LC₅₀ = 35.69 µM; MIC = 62.5 µg/ml), while A6 exhibited potent antimalarial effects (IC₅₀ = 0.58 µg/ml), and A10 demonstrated the highest antibacterial activity. The antioxidant profile revealed A8 and A2 as strong radical scavengers via DPPH and ABTS assays. Structure–activity relationship (SAR) analysis indicated that electron-withdrawing groups favored trypanocidal activity but often increased cytotoxicity, whereas electron-donating or moderately lipophilic substituents improved selectivity. Notably, most compounds exhibited low toxicity in J774A macrophages, yielding favorable selectivity indices. Collectively, these findings highlight thiadiazole–thiocoumarin hybrids as versatile scaffolds for developing next-generation antiparasitic and antimicrobial agents.