DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis

Mowbray, Charles E.; Braillard, Stéphanie; Glossop, Paul A.; Whitlock, Gavin A.; Jacobs, Robert T.; Speake, Jason D.; Pandi, Bharathi; Nare, Bakela; Maes, Louis; Yardley, Vanessa; Freund, Yvonne R.; Wall, Richard J.; Carvalho, Sandra; Bello, Davide; Kerkhof, Magali Van den; Caljon, Guy; Gilbert, Ian H.; Corpas‐López, Victoriano; Lukac, Iva; Patterson, Stephen; Zuccotto, Fabio; Wyllie, Susan

doi:10.1021/acs.jmedchem.1c01437

Cited by 34 publications

(32 citation statements)

References 28 publications

(127 reference statements)

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“…Previous work from our laboratories have identified a novel class of boron-containing molecules, the benzoxaboroles 5 , 6 as having potent activity against protozoans including Trypanosoma brucei 7 , Leishmania donovani 8 and Plasmodium falciparum 9 . Screening of the Anacor benzoxaborole compound library against T. cruzi revealed several hits, but initial assessment of structure-activity relationships (SARs) suggested limited opportunity for improvement of potency and/or selectivity, particularly in those subclasses previously found to have activity against T. brucei and L. donovani .…”

Section: Mainmentioning

confidence: 99%

Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates

Padilla

Wang

Akama³

et al. 2022

Nat Microbiol

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Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA processing pathway in T. cruzi. AN15368 was found to be active in vitro and in vivo against a range of genetically distinct T. cruzi lineages and was uniformly curative in non-human primates (NHPs) with long-term naturally acquired infections. Treatment in NHPs also revealed no detectable acute toxicity or long-term health or reproductive impact. Thus, AN15368 is an extensively validated and apparently safe, clinically ready candidate with promising potential for prevention and treatment of Chagas disease.

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Section: Mainmentioning

confidence: 99%

Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates

Padilla

Wang

Akama³

et al. 2022

Nat Microbiol

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“…Other compounds in clinical development include the oxaborole DNDI-6148 (ref. 57 ), which, like acoziborole, targets CPSF3, and the nitroimidazole DNDI-0690 (refs. 58 , 59 ), the mechanism of action of which is yet to be determined.…”

Section: Compounds and Targetsmentioning

confidence: 99%

Anti-trypanosomatid drug discovery: progress and challenges

et al. 2022

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Leishmaniasis (visceral and cutaneous), Chagas disease and human African trypanosomiasis cause substantial death and morbidity, particularly in low- and middle-income countries. Although the situation has improved for human African trypanosomiasis, there remains an urgent need for new medicines to treat leishmaniasis and Chagas disease; the clinical development pipeline is particularly sparse for Chagas disease. In this Review, we describe recent advances in our understanding of the biology of the causative pathogens, particularly from the drug discovery perspective, and we explore the progress that has been made in the development of new drug candidates and the identification of promising molecular targets. We also explore the challenges in developing new clinical candidates and discuss potential solutions to overcome such hurdles.

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“…The benzoxaborole DNDI-6148 ( Figure 4 b) has been recognized as a promising lead against both Chagas disease and VL. The oral administration of DNDI-6148 was as curative as miltefosine in mice at a minimum dose of 25 mg/kg/day bid after a 10-day treatment, without toxic side effects [ 129 , 130 , 131 ]. This remarkable efficacy is currently being evaluated for first-in-human trials of safety, tolerability and pharmacokinetics after a single ascending oral dose ( ; accessed on 3 March 2023).…”

Section: New Drugs Entering Clinical Trials Against Trypanosomatid-bo...mentioning

confidence: 99%

Further Investigations of Nitroheterocyclic Compounds as Potential Antikinetoplastid Drug Candidates

et al. 2023

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Due to the lack of specific vaccines, management of the trypanosomatid-caused neglected tropical diseases (sleeping sickness, Chagas disease and leishmaniasis) relies exclusively on pharmacological treatments. Current drugs against them are scarce, old and exhibit disadvantages, such as adverse effects, parenteral administration, chemical instability and high costs which are often unaffordable for endemic low-income countries. Discoveries of new pharmacological entities for the treatment of these diseases are scarce, since most of the big pharmaceutical companies find this market unattractive. In order to fill the pipeline of compounds and replace existing ones, highly translatable drug screening platforms have been developed in the last two decades. Thousands of molecules have been tested, including nitroheterocyclic compounds, such as benznidazole and nifurtimox, which had already provided potent and effective effects against Chagas disease. More recently, fexinidazole has been added as a new drug against African trypanosomiasis. Despite the success of nitroheterocycles, they had been discarded from drug discovery campaigns due to their mutagenic potential, but now they represent a promising source of inspiration for oral drugs that can replace those currently on the market. The examples provided by the trypanocidal activity of fexinidazole and the promising efficacy of the derivative DNDi-0690 against leishmaniasis seem to open a new window of opportunity for these compounds that were discovered in the 1960s. In this review, we show the current uses of nitroheterocycles and the novel derived molecules that are being synthesized against these neglected diseases.

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DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis

Cited by 34 publications

References 28 publications

Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates

Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates

Anti-trypanosomatid drug discovery: progress and challenges

Further Investigations of Nitroheterocyclic Compounds as Potential Antikinetoplastid Drug Candidates

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