title: Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis.
abstract: 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Thompson
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: O'Connor
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Adrian
authors.initials: A
authors.lastname: Blaser
authors.affiliation: Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine , Keppel Street, London WC1E 7HT, United Kingdom.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.affiliation: Division of Parasitology, CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Suman
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Drugs for Neglected Diseases Initiative, 15 Chemin Louis Dunant, 1202 Geneva, Switzerland.
authors.forename: Delphine
authors.initials: D
authors.lastname: Launay
authors.affiliation: Drugs for Neglected Diseases Initiative, 15 Chemin Louis Dunant, 1202 Geneva, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Martin
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Global Alliance for TB Drug Development, 40 Wall Street, New York 10005, United States.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006224:Cricetinae; D058492:Drug Repositioning; D005260:Female; D057166:High-Throughput Screening Assays; D006863:Hydrogen-Ion Concentration; D018314:Leishmania infantum / Q000187:drug effects; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D000995:Antitubercular Agents