Second-generation nitazoxanide derivatives: thiazolides are effective inhibitors of the influenza A virus

Author:

Stachulski Andrew V1,Santoro M Gabriella2,Piacentini Sara2,Belardo Giuseppe2,Frazia Simone La2,Pidathala Chandrakala1,Row Eleanor C34,Berry Neil G1,Iqbal Mazhar35,Allman Sarah A67,Semple J Edward89,Eklov Brian M10,O'Neill Paul M1,Rossignol Jean-Francois1112

Affiliation:

1. Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK

2. Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy

3. At time of writing: Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK

4. ARCINOVA, Taylor Drive, Alnwick, Northumberland, NE 66 2DH, UK

5. Health Biotechnology Division, National Institute for Biotechnology & Genetic Engineering (NIBGE), Faisalabad, Pakistan

6. Department of Life, Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA UK

7. At time of writing: Reading School of Pharmacy, Whiteknights, Reading, RG6 6AP, UK

8. Rapafusyn Pharmaceuticals, 800 W. Baltimore St., Suite 406, Baltimore, MD 21201, USA

9. At time of writing: Romark Laboratories, LC, Tampa, FL 33607, USA

10. Kalexsyn, 4502 Campus Drive, Kalamazoo, MI 49008, USA

11. Romark Laboratories, LC, Tampa, FL 33607, USA

12. Division of Infectious Diseases & International Medicine, Department of Medicine, University of South Florida College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA

Abstract

Aim: The only small molecule drugs currently available for treatment of influenza A virus (IAV) are M2 ion channel blockers and sialidase inhibitors. The prototype thiazolide, nitazoxanide, has successfully completed Phase III clinical trials against acute uncomplicated influenza. Results: We report the activity of seventeen thiazolide analogs against A/PuertoRico/8/1934(H1N1), a laboratory-adapted strain of the H1N1 subtype of IAV, in a cell culture-based assay. A total of eight analogs showed IC50s in the range of 0.14–5.0 μM. Additionally a quantitative structure–property relationship study showed high correlation between experimental and predicted activity based on a molecular descriptor set. Conclusion: A range of thiazolides show useful activity against an H1N1 strain of IAV. Further evaluation of these molecules as potential new small molecule therapies is justified.

Publisher

Future Science Ltd

Subject

Drug Discovery,Pharmacology,Molecular Medicine

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