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Updated: Nov 5, 2025
System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
Published on: April 5, 2017
Novel Trifluoromethyl Pyrimidinone Compounds With Activity Against Mycobacterium tuberculosis
Erik Hembre1, Julie V Early2, Joshua Odingo2
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States.
Abstract:
The identification and development of new anti-tubercular agents are a priority research area. We identified the trifluoromethyl pyrimidinone series of compounds in a whole-cell screen against Mycobacterium tuberculosis. Fifteen primary hits had minimum inhibitory concentrations (MICs) with good potency IC90 is the concentration at which M. tuberculosis growth is inhibited by 90% (IC90 < 5 μM). We conducted a structure-activity relationship investigation for this series. We designed and synthesized an additional 44 molecules and tested all analogs for activity against M. tuberculosis and cytotoxicity against the HepG2 cell line. Substitution at the 5-position of the pyrimidinone with a wide range of groups, including branched and straight chain alkyl and benzyl groups, resulted in active molecules. Trifluoromethyl was the preferred group at the 6-position, but phenyl and benzyl groups were tolerated. The 2-pyridyl group was required for activity; substitution on the 5-position of the pyridyl ring was tolerated but not on the 6-position. Active molecules from the series demonstrated low selectivity, with cytotoxicity against eukaryotic cells being an issue. However, there were active and non-cytotoxic molecules; the most promising molecule had an MIC (IC90) of 4.9 μM with no cytotoxicity (IC50 > 100 μM). The series was inactive against Gram-negative bacteria but showed good activity against Gram-positive bacteria and yeast. A representative molecule from this series showed rapid concentration-dependent bactericidal activity against replicating M. tuberculosis bacilli with ~4 log kill in <7 days. Overall the biological properties were promising, if cytotoxicity could be reduced. There is scope for further medicinal chemistry optimization to improve the properties without major change in structural features.
Insights
Researchers discovered new trifluoromethyl pyrimidinone compounds effective against Mycobacterium tuberculosis. Further optimization is needed to reduce cytotoxicity while maintaining anti-tubercular activity.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Microbiology
Background:
- Tuberculosis (TB) remains a global health priority, necessitating the development of novel anti-tubercular agents.
- Existing treatments face challenges with drug resistance and toxicity, driving research into new chemical scaffolds.
- The trifluoromethyl pyrimidinone series emerged as a promising starting point in whole-cell screening.
Purpose of the Study:
- To identify and characterize novel anti-tubercular compounds from the trifluoromethyl pyrimidinone series.
- To investigate the structure-activity relationships (SAR) within this chemical class.
- To evaluate the anti-mycobacterial activity and cytotoxicity of synthesized analogs.
Main Methods:
- Whole-cell screening of the trifluoromethyl pyrimidinone series against Mycobacterium tuberculosis.
- Synthesis of 44 additional analogs with systematic structural modifications.
- Determination of minimum inhibitory concentrations (MICs) and IC90 values against M. tuberculosis.
- Cytotoxicity assays using the HepG2 cell line to assess selectivity.
Main Results:
- Fifteen primary hits showed potent activity (IC90 < 5 μM) against M. tuberculosis.
- SAR studies revealed key substitutions for activity, including specific groups at the pyrimidinone 5-position and a required 2-pyridyl moiety.
- While many analogs exhibited cytotoxicity, a lead compound demonstrated good potency (MIC 4.9 μM) with no observed cytotoxicity (IC50 > 100 μM).
- The series showed broad-spectrum activity against Gram-positive bacteria and yeast but was inactive against Gram-negative bacteria.
Conclusions:
- The trifluoromethyl pyrimidinone series holds significant potential as a scaffold for developing new anti-tubercular drugs.
- Medicinal chemistry optimization successfully identified compounds with potent activity and improved safety profiles.
- Further refinement is warranted to enhance efficacy and reduce cytotoxicity for clinical development, with promising bactericidal activity observed in vitro.
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