Miniaturized Synthesis Platform for Exploring Pyrazolyl Urea Derivatives as Anti-Kinetoplastid Agents

The lack of safe, broadly effective and accessible drugs remains a challenge for treatment of Neglected Tropical Diseases. Pyrazolyl ureas have emerged as a promising scaffold for development of new drug for Chagas disease, Human African Trypanosomiasis, and Leishmaniasis.¹ To accelerate SAR studies and hit identification, a miniaturized parallel synthesis (MPS) approach was applied to generate derivatives, followed by a direct-to-biology (D2B) strategy in which crude mixtures demonstrating ≥70% conversion were directly tested in phenotypic assays.² Method reliability was assessed by synthesizing compounds with known  inhibition data against T. cruzi and L. infantum. The workflow was then applied to new compounds, leading to identification of multiple non-cytotoxic submicromolar selective hits against T. b. rhodesiense and L. infantum, which are currently being resynthesized and purified for full IC₅₀ determination and further platform validation. This work demonstrates how MPS and D2B can accelerate NTD drug discovery while reducing resource consumption and waste.