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Discovery of novel integrase-LEDGF/p75 allosteric inhibitors based on a benzene scaffold

2020; Elsevier BV; Volume: 28; Issue: 17 Linguagem: Inglês

10.1016/j.bmc.2020.115643

1464-3391

Shuichi Sugiyama, Tsutomu Iwaki, Yoshinori Tamura, Kenji Tomita, Eriko Matsuoka, Shuhei Arita, Takahiro Seki, Tomokazu Yoshinaga, Takashi Kawasuji,

HIV Research and Treatment

We report herein the discovery of novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a benzene scaffold 3. This scaffold can extend substituents from the C1 position unlike the common pyridine scaffolds 2. Structure-activity relationship studies showed that the sulfonamide linker at the C1 position was important for the antiviral activity. Interaction between sulfonamide and Q95 was observed by X-ray crystallography. Compound 31h showed more potent antiviral activity (EC50 (NL432) = 3.9 nM) than BI-224436 (EC50 (NL432) = 56 nM), suggesting the potential of the newly designed scaffold 3.