New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc ₁ complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc ₁ complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.

Cutaneous, muco-cutaneous and visceral leishmaniasis occur due to an infection with the protozoan parasite Leishmania. The current therapeutic options are limited mainly due to extensive toxicity, ...

Recent advancements in tissue engineering and stem cell science have positioned bone disease treatment as a promising frontier in regenerative medicine. This review explores the hormonal and signaling pathways critical to bone regeneration, with a focus on their clinical relevance. Key endocrine factors, including thyroid hormones (T3 and T4), insulin-like growth factor 1 (IGF-1), bone morphogenetic proteins (BMPs), parathyroid hormone (PTH), calcitonin, and fibroblast growth factor 23 (FGF23), play pivotal roles in bone remodeling by regulating osteoblast activity, bone resorption, and mineralization. These factors primarily act through the Wnt/β-catenin, BMP, and FGF signaling pathways, which govern bone repair and regeneration. While animal models, such as axolotls, zebrafish, and Xenopus laevis, provide valuable findings about these mechanisms, translating these findings into human applications presents challenges. This review underscores the therapeutic potential of modulating these hormonal networks to enhance bone regeneration while cautioning against possible adverse effects, such as uncontrolled tissue proliferation or metabolic imbalances. By integrating knowledge from regenerative models, this work provides a foundation for optimizing hormone-based therapies for clinical applications in bone repair and disease treatment.

Giardia duodenalis is the causative agent of the neglected diarrhoeal disease giardiasis. While often self-limiting, giardiasis is ubiquitous and impacts hundreds of millions of people annually. It is also a common gastro-intestinal disease of domestic pets, wildlife, and livestock animals. However, despite this impact, there is no vaccine for Giardia currently available. In addition, treatment relies on chemotherapies that are associated with increasing failure rates. To identify new treatment options for giardiasis we recently screened the Compounds Australia Scaffold Library for new chemotypes with selective anti-Giardia activity, identifying three compounds with sub-μM activity and promising selectivity. Here we extended these studies by examining the anti-Giardia activity of series CL9569 compounds. This compound series was of interest given the promising activity (IC₅₀ 1.2 μM) and selectivity demonstrated by representative compound, SN00798525 (1). Data from this work has identified an additional three thieno [3,2-b]pyrrole 5-carboxamides with anti-Giardia activity, including 2 which displayed potent cytocidal (IC₅₀ ≤ 10 nM) and selective activity against multiple Giardia strains, including representatives from both human-infecting assemblages and metronidazole resistant parasites. Preclinical studies in mice also demonstrated that 2 is well-tolerated, does not impact the normal gut microbiota and can reduce Giardia parasite burden in these animals.

The drug discovery pipeline for neglected kinetoplastid diseases remains sparse. In particular, the field of leishmaniasis drug discovery has had limited success in translating potential drug candidates into viable therapies. Here, we describe the development of two lead compounds, BZ-1 and BZ1-I, which have potent in vitro anti-leishmanial activity against Leishmania donovani DD8 intracellular amastigotes (0.59 ± 0.13 µM and 0.40 ± 0.38 µM) with corresponding selectivity ( > 33.89 and > 49.12) for differentiated THP-1 cells (Human monocytic cell line), respectively. Further characterization and biological profiling identified that in addition to the activity against L. donovani DD8 (Old World - Indian strain), compounds were active against intracellular parasites from other species and strains of the Old and New World, namely L. donovani (Old World - Sudanese strain) and L. infantum chagasi (New World-South American strain). In vivo evaluation using the hamster model illustrated that the activity observed in vitro was translated in vivo, with outstanding results. Our data suggests that these compounds represent a promising starting point for developing a novel lead series for future anti-leishmanial therapeutics.

The protozoan parasites Trypanosoma brucei and T. cruzi cause African sleeping sickness and Chagas disease, respectively. SAR for antitrypanosomal 2-[(phenylheteroaryl)ethyl]amides and ureas was expanded, identifying promising oxazoles and pyrazoles.