opc-67683 and Leishmaniasis--Visceral

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.

Topics: Animals; Antiprotozoal Agents; Antitubercular Agents; Cricetinae; Drug Repositioning; Female; High-Throughput Screening Assays; Hydrogen-Ion Concentration; Leishmania infantum; Leishmaniasis, Visceral; Mesocricetus; Mice; Mice, Inbred BALB C; Microsomes, Liver; Models, Molecular; Solubility; Structure-Activity Relationship

There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg(-1) for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg(-1) than at 3 mg kg(-1) (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL.

Topics: Administration, Oral; Animals; Antiprotozoal Agents; Antitubercular Agents; Biotransformation; Disease Models, Animal; Drug Administration Schedule; Drug Dosage Calculations; Drug Repositioning; Female; Hormesis; Leishmania donovani; Leishmaniasis, Visceral; Mice; Mice, Inbred BALB C; Nitroimidazoles; Oxazoles; Parasitic Sensitivity Tests; Treatment Outcome