Broad activity of diphenyleneiodonium analogues against Mycobacterium tuberculosis, malaria parasites and bacterial pathogens

Nghi Nguyen; Danny W Wilson; Gayathri Nagalingam; James A Triccas; Elena K Schneider; Jian Li; Tony Velkov; Jonathan Baell

doi:10.1016/j.ejmech.2017.10.010

Broad activity of diphenyleneiodonium analogues against Mycobacterium tuberculosis, malaria parasites and bacterial pathogens

Eur J Med Chem. 2018 Mar 25:148:507-518. doi: 10.1016/j.ejmech.2017.10.010. Epub 2017 Oct 6.

Authors

Nghi Nguyen¹, Danny W Wilson², Gayathri Nagalingam³, James A Triccas³, Elena K Schneider¹, Jian Li⁴, Tony Velkov⁵, Jonathan Baell⁶

Affiliations

¹ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences Monash University, VIC, 3052, Australia.
² Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide 5005, Australia; Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria 3004, Australia.
³ Microbial Pathogenesis and Immunity Group, Discipline of Infectious Diseases and Immunology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
⁴ Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, VIC, 3800, Australia.
⁵ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences Monash University, VIC, 3052, Australia. Electronic address: Tony.Velkov@monash.edu.
⁶ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences Monash University, VIC, 3052, Australia; School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing 211816, People's Republic of China. Electronic address: Jonathan.Baell@monash.edu.

PMID: 29269132
DOI: 10.1016/j.ejmech.2017.10.010

Abstract

In this study, a structure-activity relationship (SAR) compound series based on the NDH-2 inhibitor diphenyleneiodonium (DPI) was synthesised. Compounds were evaluated primarily for in vitro efficacy against Gram-positive and Gram-negative bacteria, commonly responsible for nosocomial and community acquired infections. In addition, we also assessed the activity of these compounds against Mycobacterium tuberculosis (Tuberculosis) and Plasmodium spp. (Malaria). This led to the discovery of highly potent compounds active against bacterial pathogens and malaria parasites in the low nanomolar range, several of which were significantly less toxic to mammalian cells.

Keywords: Diphenyleneiodonium; Gram-negative; Malaria; Plasmodium; Type II NADH-quinone oxidoreductase.

MeSH terms

Animals
Bacteria / drug effects*
Bacteria / pathogenicity
Community-Acquired Infections / drug therapy
Cross Infection / drug therapy
Gram-Negative Bacteria / drug effects
Gram-Positive Bacteria / drug effects
Malaria / drug therapy*
Malaria / parasitology
Mycobacterium tuberculosis / drug effects*
Onium Compounds / chemistry
Onium Compounds / pharmacology*
Structure-Activity Relationship

Substances

Onium Compounds
diphenyleneiodonium