Publication date: Sep 15, 2025
COVID-19 highlighted urgent need for broad-spectrum antivirals. Nitazoxanide (NTZ), a broad-spectrum antiviral with an established safety profile, shows promise against SARS-CoV-2; however, its moderate potency and pharmacokinetic limitations necessitate the development of improved analogues. We synthesized 24 thiazolide analogues, including novel molecules bearing 4′- or 5′-aryl substitutions, dual 4′,5′-modifications, or fused benzothiazole cores, and evaluated their in vitro efficacy against SARS-CoV-2 (Vero E6 cells). Antiviral potency (IC), cytotoxicity (CC), and selectivity indices (SI = CC/IC) were determined by qRT-PCR and MTT assays. In silico ADMET profiling predicted drug-likeness, absorption, distribution, metabolism, excretion, and toxicity. Among the analogues, 4′-aryl thiazolides (6d-6 g) and one dual-substituted thiazolide (7b) exhibited outstanding selectivity index (SI > 30), significantly surpassing NTZ (SI ≈ 14). The analogue 6e (3-OCF-phenyl) demonstrated the highest SI of ≈ 51 (IC ≈0. 21 uM; CC ≈10. 8 uM). Benzothiazole analogue 8a (OCF at 4′-position) also showed favorable SI (≈11). ADMET predictions confirmed acceptable oral bioavailability, minimal cytochrome P450 (CYP450) inhibition, and low cardiotoxicity risk. Lipophilic, electron-withdrawing substituents at C-4 of the thiazole core markedly enhance antiviral potency and therapeutic potential. In particular, 4′-(PhOCF) substitutions emerge as lead scaffolds for further preclinical development. These insights provide a way forward for optimizing thiazolides against SARS-CoV-2 and other emerging viruses.
| Concepts | Keywords |
|---|---|
| Benzothiazole | benzothiazolides |
| Bioavailability | broad-spectrum antivirals |
| Cardiotoxicity | nitazoxanide analogues |
| Cyp450 | SARS-CoV-2 |
| Future | Thiazolides |
Semantics
| Type | Source | Name |
|---|---|---|
| drug | DRUGBANK | Nitazoxanide |
| drug | DRUGBANK | BENZOTHIAZOLE |
| pathway | REACTOME | Metabolism |