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  3. Design and synthesis of novel and potent allosteric HIV-1 integrase inhibitors with a spirocyclic moiety

Design and synthesis of novel and potent allosteric HIV-1 integrase inhibitors with a spirocyclic moiety

  • Bioorg Med Chem Lett. 2024 Jun 26:110:129864. doi: 10.1016/j.bmcl.2024.129864.
Kaoru Adachi 1,  Tomoyuki Manabe 2,  Takayuki Yamasaki 3,  Akira Suma 2,  Takuya Orita 4,  Tomoko Furuzono 4,  Tsuyoshi Adachi 4,  Yoshitsugu Ohata 5,  Yoshiyuki Akiyama 6,  Susumu Miyazaki 4
Affiliations

Affiliations

  • 1 Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. Electronic address: kaoru.adachi@jt.com.
  • 2 Innovation to Implementation Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • 3 Department of Research Planning, Preclinical, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • 4 Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • 5 Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • 6 DMPK Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
PMID: 38942126 DOI: 10.1016/j.bmcl.2024.129864
Abstract

We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility of the conformation of the lipophilic part of the inhibitor. Compound 5 showed Antiviral activity by binding to the nuclear lens epithelium-derived growth factor (LEDGF/p75) binding site of HIV-1 integrase (IN). The introduction of a lipophilic amide substituent into the central benzene ring resulted in a significant increase in Antiviral activity against HIV-1 WT X-ray crystallography of compound 15 in complex with the integrase revealed the presence of a hydrogen bond between the oxygen atom of the amide of compound 15 and the hydroxyl group of the T125 side chain. Chiral compound 17 showed high Antiviral activity, good bioavailability, and low clearance in rats.

Keywords

Allosteric inhibitor; HIV-1 integrase; LEDGF/p75.

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