Structure–Activity Relationship Study of Benzamides as Mycobacterium tuberculosis QcrB Inhibitors

Brock E. Lynde; Jared Mattos; Danielle M. Chemaly; Aditi Deshpande; Sreekanth Reddy Pogula; Eric Greve; Sultan Chowdhury; Tanya Parish

doi:10.1021/acsmedchemlett.5c00252

Structure–Activity Relationship Study of Benzamides as Mycobacterium tuberculosis QcrB Inhibitors

Brock E. Lynde
, Jared Mattos
, Danielle M. Chemaly
, Aditi Deshpande
, Sreekanth Reddy Pogula
, Eric Greve
, Sultan Chowdhury
, Tanya Parish

Seattle Biomedical Research Institute
University of Washington

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

Abstract

We previously identified a morpholinobenzamide series with potent activity against Mycobacterium tuberculosis. We conducted structure–activity relationship studies focusing on removing the metabolically labile morpholine group while retaining antibacterial activity. We identified potent benzamides 16 (IC₉₀= 0.13 μM) and 22f (IC₉₀= 0.09 μM) with a thiophene and methyl substituents replacing the morpholine at the C-5 position. These analogs had high selectivity (selectivity index = 300 and 278, respectively) and low cytotoxicity (HepG2 CC₅₀of 39 and 25 μM, respectively). Compound 16 demonstrated a good metabolic stability in human liver microsomes.

Original language	English
Pages (from-to)	1610-1618
Number of pages	9
Journal	ACS Medicinal Chemistry Letters
Volume	16
Issue number	8
DOIs	https://doi.org/10.1021/acsmedchemlett.5c00252
Publication status	Published - 14 Aug 2025
Externally published	Yes

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

aerobic respiration
antibacterial
mycobacteria
tuberculosis

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10.1021/acsmedchemlett.5c00252

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title = "Structure–Activity Relationship Study of Benzamides as Mycobacterium tuberculosis QcrB Inhibitors",

abstract = "We previously identified a morpholinobenzamide series with potent activity against Mycobacterium tuberculosis. We conducted structure–activity relationship studies focusing on removing the metabolically labile morpholine group while retaining antibacterial activity. We identified potent benzamides 16 (IC90= 0.13 μM) and 22f (IC90= 0.09 μM) with a thiophene and methyl substituents replacing the morpholine at the C-5 position. These analogs had high selectivity (selectivity index = 300 and 278, respectively) and low cytotoxicity (HepG2 CC50of 39 and 25 μM, respectively). Compound 16 demonstrated a good metabolic stability in human liver microsomes.",

keywords = "aerobic respiration, antibacterial, mycobacteria, tuberculosis",

author = "Lynde, \{Brock E.\} and Jared Mattos and Chemaly, \{Danielle M.\} and Aditi Deshpande and Pogula, \{Sreekanth Reddy\} and Eric Greve and Sultan Chowdhury and Tanya Parish",

year = "2025",

month = aug,

day = "14",

doi = "10.1021/acsmedchemlett.5c00252",

language = "English",

volume = "16",

pages = "1610--1618",

journal = "ACS Medicinal Chemistry Letters",

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TY - JOUR

T1 - Structure–Activity Relationship Study of Benzamides as Mycobacterium tuberculosis QcrB Inhibitors

AU - Lynde, Brock E.

AU - Mattos, Jared

AU - Chemaly, Danielle M.

AU - Deshpande, Aditi

AU - Pogula, Sreekanth Reddy

AU - Greve, Eric

AU - Chowdhury, Sultan

AU - Parish, Tanya

PY - 2025/8/14

Y1 - 2025/8/14

N2 - We previously identified a morpholinobenzamide series with potent activity against Mycobacterium tuberculosis. We conducted structure–activity relationship studies focusing on removing the metabolically labile morpholine group while retaining antibacterial activity. We identified potent benzamides 16 (IC90= 0.13 μM) and 22f (IC90= 0.09 μM) with a thiophene and methyl substituents replacing the morpholine at the C-5 position. These analogs had high selectivity (selectivity index = 300 and 278, respectively) and low cytotoxicity (HepG2 CC50of 39 and 25 μM, respectively). Compound 16 demonstrated a good metabolic stability in human liver microsomes.

AB - We previously identified a morpholinobenzamide series with potent activity against Mycobacterium tuberculosis. We conducted structure–activity relationship studies focusing on removing the metabolically labile morpholine group while retaining antibacterial activity. We identified potent benzamides 16 (IC90= 0.13 μM) and 22f (IC90= 0.09 μM) with a thiophene and methyl substituents replacing the morpholine at the C-5 position. These analogs had high selectivity (selectivity index = 300 and 278, respectively) and low cytotoxicity (HepG2 CC50of 39 and 25 μM, respectively). Compound 16 demonstrated a good metabolic stability in human liver microsomes.

KW - aerobic respiration

KW - antibacterial

KW - mycobacteria

KW - tuberculosis

U2 - 10.1021/acsmedchemlett.5c00252

DO - 10.1021/acsmedchemlett.5c00252

M3 - Letter

AN - SCOPUS:105009695043

SN - 1948-5875

VL - 16

SP - 1610

EP - 1618

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 8

ER -

Structure–Activity Relationship Study of Benzamides as Mycobacterium tuberculosis QcrB Inhibitors

Abstract

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Keywords

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