Structure-based development of N-Arylindole derivatives as Pks13 inhibitors against Mycobacterium tuberculosis

Xuan Zhang; Shichun Lun; Yu Xin Li; Wei Zhang; Ruo Yi Zhou; Ting Liu; Fan Yang; Jie Tang; William R. Bishai; Li Fang Yu

doi:10.1016/j.ejmech.2024.117148

Structure-based development of N-Arylindole derivatives as Pks13 inhibitors against Mycobacterium tuberculosis

Xuan Zhang
, Shichun Lun
, Yu Xin Li
, Wei Zhang
, Ruo Yi Zhou
, Ting Liu
, Fan Yang
, Jie Tang
, William R. Bishai^*
, Li Fang Yu^*

^*Corresponding author for this work

School of Chemistry and Molecular Engineering

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Targeting the biosynthetic pathway of mycolic acid is highly attractive to researchers in the field of novel anti-tubercular drug development. Pks13-TE is an essential catalytic component in the last assembling step of mycolic acid, and the co-crystal structures of the Pks13-TE-inhibitor complex provide insight into ligand recognition. Based on a structure-guided strategy, N-aryl indole derivatives were designed, synthesized, and evaluated for their antitubercular activities. Compound 44 was identified as the most promising compound with high potency against M. tb H37Rv (MIC = 0.07 μM) and a favorable metabolic profile in human liver microsomes. Moreover, compound 44 exhibited oral bioavailability in a serum inhibition titration (SIT) assay, which warrants further development.

Original language	English
Article number	117148
Journal	European Journal of Medicinal Chemistry
Volume	283
DOIs	https://doi.org/10.1016/j.ejmech.2024.117148
State	Published - 5 Feb 2025

Keywords

Antitubercular agents
N-Aryl indole
Pks13 inhibitor
Structure-guided optimization

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2024.117148

Cite this

@article{dc67797dc694418faf632bf6e4cde703,

title = "Structure-based development of N-Arylindole derivatives as Pks13 inhibitors against Mycobacterium tuberculosis",

abstract = "Targeting the biosynthetic pathway of mycolic acid is highly attractive to researchers in the field of novel anti-tubercular drug development. Pks13-TE is an essential catalytic component in the last assembling step of mycolic acid, and the co-crystal structures of the Pks13-TE-inhibitor complex provide insight into ligand recognition. Based on a structure-guided strategy, N-aryl indole derivatives were designed, synthesized, and evaluated for their antitubercular activities. Compound 44 was identified as the most promising compound with high potency against M. tb H37Rv (MIC = 0.07 μM) and a favorable metabolic profile in human liver microsomes. Moreover, compound 44 exhibited oral bioavailability in a serum inhibition titration (SIT) assay, which warrants further development.",

keywords = "Antitubercular agents, N-Aryl indole, Pks13 inhibitor, Structure-guided optimization",

author = "Xuan Zhang and Shichun Lun and Li, \{Yu Xin\} and Wei Zhang and Zhou, \{Ruo Yi\} and Ting Liu and Fan Yang and Jie Tang and Bishai, \{William R.\} and Yu, \{Li Fang\}",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Masson SAS",

year = "2025",

month = feb,

day = "5",

doi = "10.1016/j.ejmech.2024.117148",

language = "英语",

volume = "283",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson s.r.l.",

}

TY - JOUR

T1 - Structure-based development of N-Arylindole derivatives as Pks13 inhibitors against Mycobacterium tuberculosis

AU - Zhang, Xuan

AU - Lun, Shichun

AU - Li, Yu Xin

AU - Zhang, Wei

AU - Zhou, Ruo Yi

AU - Liu, Ting

AU - Yang, Fan

AU - Tang, Jie

AU - Bishai, William R.

AU - Yu, Li Fang

PY - 2025/2/5

Y1 - 2025/2/5

N2 - Targeting the biosynthetic pathway of mycolic acid is highly attractive to researchers in the field of novel anti-tubercular drug development. Pks13-TE is an essential catalytic component in the last assembling step of mycolic acid, and the co-crystal structures of the Pks13-TE-inhibitor complex provide insight into ligand recognition. Based on a structure-guided strategy, N-aryl indole derivatives were designed, synthesized, and evaluated for their antitubercular activities. Compound 44 was identified as the most promising compound with high potency against M. tb H37Rv (MIC = 0.07 μM) and a favorable metabolic profile in human liver microsomes. Moreover, compound 44 exhibited oral bioavailability in a serum inhibition titration (SIT) assay, which warrants further development.

AB - Targeting the biosynthetic pathway of mycolic acid is highly attractive to researchers in the field of novel anti-tubercular drug development. Pks13-TE is an essential catalytic component in the last assembling step of mycolic acid, and the co-crystal structures of the Pks13-TE-inhibitor complex provide insight into ligand recognition. Based on a structure-guided strategy, N-aryl indole derivatives were designed, synthesized, and evaluated for their antitubercular activities. Compound 44 was identified as the most promising compound with high potency against M. tb H37Rv (MIC = 0.07 μM) and a favorable metabolic profile in human liver microsomes. Moreover, compound 44 exhibited oral bioavailability in a serum inhibition titration (SIT) assay, which warrants further development.

KW - Antitubercular agents

KW - N-Aryl indole

KW - Pks13 inhibitor

KW - Structure-guided optimization

UR - https://www.scopus.com/pages/publications/85212552309

U2 - 10.1016/j.ejmech.2024.117148

DO - 10.1016/j.ejmech.2024.117148

M3 - 文章

C2 - 39709795

AN - SCOPUS:85212552309

SN - 0223-5234

VL - 283

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 117148

ER -

Structure-based development of N-Arylindole derivatives as Pks13 inhibitors against Mycobacterium tuberculosis

Abstract

Keywords

UN SDGs

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