Discovery, synthesis, and optimization of an N-alkoxy indolylacetamide against HIV-1 carrying NNRTI-resistant mutations from the Isatis indigotica root

Chengbo Xu; Yijing Xin; Minghua Chen; Mingyu Ba; Qinglan Guo; Chenggen Zhu; Ying Guo; Jiangong Shi

doi:10.1016/j.ejmech.2020.112071

Discovery, synthesis, and optimization of an N-alkoxy indolylacetamide against HIV-1 carrying NNRTI-resistant mutations from the Isatis indigotica root

Eur J Med Chem. 2020 Mar 1:189:112071. doi: 10.1016/j.ejmech.2020.112071. Epub 2020 Jan 22.

Authors

Chengbo Xu¹, Yijing Xin¹, Minghua Chen², Mingyu Ba¹, Qinglan Guo¹, Chenggen Zhu¹, Ying Guo³, Jiangong Shi⁴

Affiliations

¹ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
² State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
³ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: yingguo6@imm.ac.cn.
⁴ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: shijg@imm.ac.cn.

Abstract

From an aqueous decoction of the traditional Chinese medicine "ban lan gen" (the Isatis indigotica root), an antiviral natural product CI - 39 was isolated as an NNRTI (non-nucleoside reverse transcriptase inhibitor) (EC₅₀ = 3.40 μM). Its novel structure was determined as methyl (1-methoxy-1H-indol-3-yl)acetamidobenzoate by spectroscopic data and confirmed by single crystal X-ray diffraction. Through synthesis and structure-activity relationship (SAR) investigation of CI - 39 and 57 new derivatives (24 with EC₅₀ values of 0.06-8.55 μM), two optimized derivatives 10f and 10i (EC₅₀: 0.06 μM and 0.06 μM) having activity comparable to that of NVP (EC₅₀ = 0.03 μM) were obtained. Further evaluation verified that 10f and 10i were RT DNA polymerase inhibitors and exhibited better activities and drug resistance folds compared to NVP against seven NNRTI-resistant strains carrying different mutations. Especially, 10i (EC₅₀ = 0.43 μM) was more active to the L100I/K103N double-mutant strain as compared to both NVP (EC₅₀ = 0.76 μM) and EFV (EC₅₀ = 1.08 μM). The molecular docking demonstrated a possible binding pattern between 10i and RT and revealed activity mechanism of 10i against the NNRTI-resistant strains.

Keywords: Derivative synthesis; HIV-1 inhibitor; Isatis indigotica; N-Alkyloxy indole derivative; NNRTI; Structure-activity relationship.

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / pharmacology
Drug Design
Drug Discovery*
Drug Resistance, Viral
HEK293 Cells
HIV Infections / drug therapy*
HIV Infections / virology
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV-1 / drug effects*
HIV-1 / enzymology
Humans
Indoleacetic Acids / chemistry
Indoles / chemical synthesis*
Indoles / pharmacology*
Isatis / chemistry*
Molecular Structure
Mutation
Plant Extracts / pharmacology
Reverse Transcriptase Inhibitors / chemical synthesis*
Reverse Transcriptase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Anti-HIV Agents
Indoleacetic Acids
Indoles
Plant Extracts
Reverse Transcriptase Inhibitors
HIV Reverse Transcriptase