Combining Microscale Parallel Synthesis (MPS) and Medium-Throughput Screening (MTS) for Accelerated Hit-to-lead Optimization of Anti-Infective Agents.

• Grant number: 23/11804-5
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: June 01, 2024
• End date: May 31, 2029
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Daniel Gedder Silva
• Grantee: Daniel Gedder Silva
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 24/22131-4 - Microscale Parallel Synthesis and Evaluation of Pyrazolyl Urea Derivatives as Potential Antitrypanosomal Agents, BP.DD; 24/22535-8 - Development and parallel microscale synthesis of heterocyclic compounds using fragment-based drug design (FBDD) as potential agents against Leishmania braziliensis, BP.MS; 24/22239-0 - Parallel Microscale Synthesis of Pyrazolo[1,5-a]pyrimidine Derivatives as Potential T Anti-trypanosomal Agents, BP.DD; + associated scholarships 24/09495-7 - Conventional synthesis of heterocycle cores for the development of a microscale synthesis platform, BP.IC; 24/09350-9 - Validation of the microscale synthesis platform., BP.IC; 24/08271-8 - Combining Microscale Parallel Synthesis (MPS) and Medium-Throughput Screening (MTS) for Accelerated Hit-to-lead Optimization of Anti-Infective Agents., BP.JP - associated scholarships

Abstract

With the aim of creating a consortium of researchers interested in designing and fastly synthesizing compounds with the required potency, safety and DMPK properties, the central idea of the project consists of a miniaturized and accelerated library synthesis and the screening of the unpurified compounds in the same format yielding rapid, high-quality hit findings. To test whether unpurified reaction mixtures can give useful screening results against parasite panels, identified hits will be resynthesized, purified and further characterized. Quality control will be followed by HPLC, mass spectrometry and quantitative NMR. As soon as the methods are fully validated, we will progress with the applicability of the Microscale Parallel Synthesis approach for late-stage functionalization to diversify the new anti-Infectives agents. The implementation and validation of the synthetic methods will demonstrate that large compound libraries can be produced without purification to an initial biological screening in a very fast fashion on a nanomole scale. Additionally, the method will contribute to reducing the costs of drug design and development and to implementing a greener process. This strong and original research proposal will establish in Brazil a new area of Medicinal Chemistry since institutions in São Paulo state do not yet have a tradition in microscale synthesis linked to biological assays as well as DMPK and mode of action for infectious diseases. (AU)