Structure-Activity relationship and optimization of drug-like properties of antituberculosis 3-(4,4-dimethyl-1,4-azasilinane)methylpyrazole MmpL3 inhibitors

Lutete Peguy Khonde; Nashied Peton; Keabetswe Masike; Tania Valentine; Frank Zindo; Stephen Fienberg; Charles Omollo; Mathew Njoroge; Francesco Vallini; Chiara Tammaro; Michela Guida; Dirk Schnappinger; Lauren Ames; Mariangela Biava; Vinayak Singh; Tanya Parish; Giovanna Poce; Sandeep R Ghorpade; Kelly Chibale

doi:10.1016/j.ejmech.2026.118841

Structure-Activity relationship and optimization of drug-like properties of antituberculosis 3-(4,4-dimethyl-1,4-azasilinane)methylpyrazole MmpL3 inhibitors

Eur J Med Chem. 2026 Aug 5:312:118841. doi: 10.1016/j.ejmech.2026.118841. Epub 2026 Apr 8.

Authors

Lutete Peguy Khonde¹, Nashied Peton², Keabetswe Masike³, Tania Valentine¹, Frank Zindo¹, Stephen Fienberg¹, Charles Omollo², Mathew Njoroge³, Francesco Vallini⁴, Chiara Tammaro⁴, Michela Guida⁴, Dirk Schnappinger⁵, Lauren Ames⁶, Mariangela Biava⁴, Vinayak Singh⁷, Tanya Parish⁶, Giovanna Poce⁸, Sandeep R Ghorpade⁹, Kelly Chibale¹⁰

Affiliations

¹ Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa.
² Drug Discovery and Development Centre (H3D), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South Africa.
³ Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, University of Cape Town, Rondebosch, 7701, South Africa.
⁴ Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Piazzale A. Moro 5, Rome, 00185, Italy.
⁵ Department of Microbiology and Immunology, Weill Cornell Medical College, New York, 10065, United States.
⁶ Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98109, United States.
⁷ Drug Discovery and Development Centre (H3D), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, South Africa.
⁸ Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Piazzale A. Moro 5, Rome, 00185, Italy. Electronic address: giovanna.poce@uniroma1.it.
⁹ Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa. Electronic address: Sandeep.Ghorpade@uct.ac.za.
¹⁰ Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, South Africa. Electronic address: Kelly.Chibale@uct.ac.za.

PMID: 41996871
DOI: 10.1016/j.ejmech.2026.118841

Abstract

Structure-activity relationship studies of previously reported 3-(4,4-dimethyl-1,4-azasilinane) methylpyrazoles with potent anti-tuberculosis activity were conducted to identify leads with drug-like properties by optimizing the lipophilicity of the compounds. Removal of phenyl substituents at 1 or 5 positions of the pyrazole ring or introducing polar substituents on the 5-phenyl ring identified potent compounds with lower logD and improved solubility. Compounds with a C5-cyclopentyl substituent showed improved stability in human microsomes. In vitro and in vivo metabolite identification studies were conducted to facilitate further compound optimization. Compounds are bactericidal in vitro against replicating Mycobacterium tuberculosis (Mtb) and retain activity against drug-resistant Mtb. Profiling against the MmpL3 TetON and tet-inducible over-expression (OE) mutants confirmed direct inhibition of the MtbMmpL3 transporter as a mode-of-action of the compounds.

Keywords: Dimethylazasilinane; MmpL3; Mycobacteriumtuberculosis; Pyrazoles; Tuberculosis.

MeSH terms

Antitubercular Agents* / chemical synthesis
Antitubercular Agents* / chemistry
Antitubercular Agents* / pharmacology
Bacterial Proteins* / antagonists & inhibitors
Bacterial Proteins* / metabolism
Dose-Response Relationship, Drug
Humans
Membrane Transport Proteins* / metabolism
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis* / drug effects
Pyrazoles* / chemical synthesis
Pyrazoles* / chemistry
Pyrazoles* / pharmacology
Structure-Activity Relationship

Substances

Pyrazoles
Antitubercular Agents
MmpL3 protein, Mycobacterium tuberculosis
Bacterial Proteins
Membrane Transport Proteins