Synthetic derivatives of the antifungal drug ciclopirox are active against herpes simplex virus 2

Eur J Med Chem. 2022 Aug 5:238:114443. doi: 10.1016/j.ejmech.2022.114443.

Maryam Zangi ¹, Katherine A Donald ², Andreu Gazquez Casals ², Abaigeal D Franson ², Alice J Yu ², Elise M Marker ², Molly E Woodson ², Scott D Campbell ³, M Abdul Mottaleb ⁴, Tanguturi Venkata Narayana Hajay Kumar ⁵, Makala Shakar Reddy ⁵, Lingala Vijaya Raghava Reddy ⁵, Subir Kumar Sadhukhan ⁵, David W Griggs ⁶, Lynda A Morrison ⁷, Marvin J Meyers ⁸

Affiliations

1 Department of Chemistry, Saint Louis University, Saint Louis, MO, 63103, USA.
2 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA.
3 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA; Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO, 63103, USA. Electronic address: scampbell@loxooncology.com.
4 Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO, 63103, USA.
5 Medicinal Chemistry Division, Curia, Hyderabad, 500078, India.
6 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA; Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO, 63103, USA.
7 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA; Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO, 63103, USA. Electronic address: lynda.morrison@health.slu.edu.
8 Department of Chemistry, Saint Louis University, Saint Louis, MO, 63103, USA; Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO, 63103, USA. Electronic address: marvin.j.meyers@slu.edu.

PMID: 35635945 DOI: 10.1016/j.ejmech.2022.114443

Abstract

We previously showed that the anti-fungal drug ciclopirox olamine effectively inhibits replication of herpes simplex virus (HSV)-1 and HSV-2. Given the rise of HSV strains that are resistant to nucleos(t)ide analog treatment, as well as the incomplete efficacy of nucleos(t)ide analogs, new inhibitory compounds must be explored for potential use in the treatment of HSV Infection. In the present study, we analyzed 44 compounds derived from the core structure of ciclopirox olamine for inhibitory activity against HSV. Thirteen of these derivative compounds inhibited HSV-2 replication by > 1000- to ∼100,000-fold at 1 μM and displayed EC₅₀ values lower than that of acyclovir, as well as low cytotoxicity, indicating their strong therapeutic potential. Through structural comparison, we also provide evidence for the importance of various structural motifs to the efficacy of ciclopirox and its derivatives, namely hydrophobic groups at R⁴ and R⁶ of the ciclopirox core structure. Like ciclopirox, representative analogs exhibit some oral bioavailability but are rapidly cleared in vivo. Together, these results will guide further development of N-hydroxypyridones as HSV therapeutics.

Keywords

Acyclovir; Antiviral; Ciclopirox; HSV; Herpes simplex virus; Inhibition.

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