Antitubercular Bis-Substituted Cyclam Derivatives: Structure-Activity Relationships and in Vivo Studies

Malcolm Spain; Joseph K-H Wong; Gayathri Nagalingam; James M Batten; Elinor Hortle; Stefan H Oehlers; Xiao Fan Jiang; Hasini E Murage; Jack T Orford; Patrick Crisologo; James A Triccas; Peter J Rutledge; Matthew H Todd

doi:10.1021/acs.jmedchem.7b01569

Antitubercular Bis-Substituted Cyclam Derivatives: Structure-Activity Relationships and in Vivo Studies

J Med Chem. 2018 Apr 26;61(8):3595-3608. doi: 10.1021/acs.jmedchem.7b01569. Epub 2018 Apr 5.

Affiliations

¹ School of Chemistry , The University of Sydney , Sydney , NSW 2006 , Australia.
² Microbial Immunity and Pathogenesis Group, Department of Infectious Diseases and Immunology, Sydney Medical School , The University of Sydney , Sydney , NSW 2006 , Australia.
³ Tuberculosis Research Program , Centenary Institute, Royal Prince Alfred Hospital , Missenden Road , Camperdown, Sydney , NSW 2050 , Australia.
⁴ Central Clinical School, Sydney Medical School , The University of Sydney , Sydney , NSW 2006 , Australia.

PMID: 29558124
DOI: 10.1021/acs.jmedchem.7b01569

Abstract

We recently reported the discovery of nontoxic cyclam-derived compounds that are active against drug-resistant Mycobacterium tuberculosis. In this paper we report exploration of the structure-activity relationship for this class of compounds, identifying several simpler compounds with comparable activity. The most promising compound identified, possessing significantly improved water solubility, displayed high levels of bacterial clearance in an in vivo zebrafish embryo model, suggesting this compound series has promise for in vivo treatment of tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Aza Compounds / chemical synthesis
Aza Compounds / chemistry
Aza Compounds / pharmacology*
Bacterial Load / drug effects
Coordination Complexes / chemical synthesis
Coordination Complexes / chemistry
Coordination Complexes / pharmacology
Drug Resistance, Bacterial
Heterocyclic Compounds, 1-Ring / chemical synthesis
Heterocyclic Compounds, 1-Ring / chemistry
Heterocyclic Compounds, 1-Ring / pharmacology*
Macrocyclic Compounds / chemical synthesis
Macrocyclic Compounds / chemistry
Macrocyclic Compounds / pharmacology*
Metals, Heavy / chemistry
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium marinum / drug effects
Solubility
Structure-Activity Relationship
Tuberculosis / drug therapy
Zebrafish

Substances

Antitubercular Agents
Aza Compounds
Coordination Complexes
Heterocyclic Compounds, 1-Ring
Macrocyclic Compounds
Metals, Heavy