Novel pyridinium-type fullerene derivatives as multitargeting inhibitors of HIV-1 reverse transcriptase, HIV-1 protease, and HCV NS5B polymerase

Toi Kobayashi; Takumi Yasuno; Kyoko Takahashi; Shigeo Nakamura; Tadahiko Mashino; Tomoyuki Ohe

doi:10.1016/j.bmcl.2021.128267

Novel pyridinium-type fullerene derivatives as multitargeting inhibitors of HIV-1 reverse transcriptase, HIV-1 protease, and HCV NS5B polymerase

Bioorg Med Chem Lett. 2021 Oct 1:49:128267. doi: 10.1016/j.bmcl.2021.128267. Epub 2021 Jul 14.

Authors

Toi Kobayashi¹, Takumi Yasuno¹, Kyoko Takahashi², Shigeo Nakamura², Tadahiko Mashino¹, Tomoyuki Ohe³

Affiliations

¹ Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
² Department of Chemistry, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino, Tokyo, Japan.
³ Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan. Electronic address: ohe-tm@pha.keio.ac.jp.

PMID: 34271071
DOI: 10.1016/j.bmcl.2021.128267

Abstract

In the present study, we newly synthesized four types of novel fullerene derivatives: pyridinium/ethyl ester-type derivatives 3b-3l, pyridinium/carboxylic acid-type derivatives 4a, 4e, 4f, pyridinium/amide-type derivative 5a, and pyridinium/2-morpholinone-type derivative 6a. Among the assessed compounds, cis-3c, cis-3d, trans-3e, trans-3h, cis-3l, cis-4e, cis-4f, trans-4f, and cis-5a were found to inhibit HIV-1 reverse transcriptase (HIV-RT), HIV-1 protease (HIV-PR), and HCV NS5B polymerase (HCV NS5B), with IC₅₀ values observed in the micromolar range. Cellular uptake of pyridinium/ethyl ester-type derivatives was higher than that of corresponding pyridinium/carboxylic acid-type derivatives and pyridinium/amide-type derivatives. This result might indicate that pyridinium/ethyl ester-type derivatives are expected to be lead compounds for multitargeting drugs to treat HIV/HCV coinfection.

Keywords: Fullerene; HCV NS5B polymerase; HIV protease; HIV reverse transcriptase; Structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / pharmacology*
Anti-HIV Agents / toxicity
Cell Line, Tumor
Fullerenes / chemistry
Fullerenes / pharmacology*
Fullerenes / toxicity
HIV Protease / metabolism
HIV Protease Inhibitors / chemical synthesis
HIV Protease Inhibitors / pharmacology*
HIV Protease Inhibitors / toxicity
HIV Reverse Transcriptase / antagonists & inhibitors
HIV-1 / enzymology
Hepacivirus / enzymology
Humans
Mice
Molecular Structure
NIH 3T3 Cells
Pyridinium Compounds / chemical synthesis
Pyridinium Compounds / pharmacology*
Pyridinium Compounds / toxicity
Reverse Transcriptase Inhibitors / chemical synthesis
Reverse Transcriptase Inhibitors / pharmacology*
Reverse Transcriptase Inhibitors / toxicity
Structure-Activity Relationship
Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

Anti-HIV Agents
Fullerenes
HIV Protease Inhibitors
Pyridinium Compounds
Reverse Transcriptase Inhibitors
Viral Nonstructural Proteins
reverse transcriptase, Human immunodeficiency virus 1
NS-5 protein, hepatitis C virus
HIV Reverse Transcriptase
HIV Protease
p16 protease, Human immunodeficiency virus 1