Human immunodeficiency virus type 1 (HIV-1) is still a major public health concern. Highly active antiretroviral therapy (HAART) is a combination of antiretroviral drugs targeting the virus at multiple stages of its replication cycle which has helped reduce new HIV infections as well as AIDS-related deaths. However, its routine application has led to multi-drug resistance and the onset of adverse side-effects that results from long-term use. It is therefore crucial to continue the development of novel antivirals, particularly those that are inexpensive, nontoxic, and which are unlikely to result in viral resistance. Mercaptobenzamide molecules like Amovir (Fig. 1) are chemically simple HIV inactivators targeting viral nucleocapsid protein 7 (NCp7), a 55 amino acid protein that performs essential functions during the assembly and maturation of new HIV virions. This class of molecule also shows low toxicity, and a high barrier to viral resistance. We developed Nipamovir (Fig. 1), a prodrug which protects the sulfur atom of Amovir in a manner similar to the clinically used immunosuppressant Azathioprine. Our molecule is very simple to reproducibly synthesize and has similar antiviral activity compared to Amovir and other mercaptobenzamides. Here we report the synthesis, in-vitro and in-vivo preclinical evaluation of Nipamovir.

Nipamovir: Synthesis and preclinical evaluation of an anti-HIV thioether benzamide prodrug

ACS Fall 2021

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