Wang, Yinuo; (2025) Open Source Malaria: Potent Aminothienopyrimidine-based Antiplasmodium Agents with Novel Mechanism of Action and Cross-Screening Potential Against Multiple Pathogens. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Malaria continues to impose a major global health burden, necessitating the develop- ment of antimalarial agents with novel mechanisms of action to address the ongoing threat of drug resistance. Since 2011, the Todd group has pioneered the application of open science principles to antimalarial drug discovery through the Open Source Malaria consortium, with all experimental data and biological results shared in real time in a fully transparent framework. This thesis describes the design, synthesis, and mechanistic evaluation of novel thienopyrimidine-based compounds within the Open Source Malaria Series 3 project. The in vitro biological activity of these compounds against Plasmodium falciparum is reported alongside investigations into their mechanism of action. Chapter 1 provides an overview of malaria pathophysiology and summarises historical and current antimalarial therapies, with particular emphasis on the identification of novel molecular targets that have emerged over recent decades. The rationale and practice of open science are introduced, highlighting the collaborative workflows and real-time data dissemination underpinning the Open Source Malaria initiative. In Chapter 2, reaction hijacking is explored as a novel chemical strategy for targeting P. falciparum aminoacyl-tRNA synthetases (aaRSs), focusing on asparaginyl-tRNA synthetase (PfAsnRS). The lead compound OSM-S-106 (below) was resynthesised and comprehensively characterised, confirming its covalent hijacking mechanism whereby the enzyme catalyses the formation of a stable asparagine–OSM-S-106 adduct in the active site. Structure-activity relationship (SAR) studies revealed that subtle mod- ifications to the sulfonamide moiety markedly influenced potency, underscoring the sensitivity of the hijacking mechanism to precise electronic and steric features. Building upon these mechanistic insights, a systematic panel of OSM-S-106–amino acid conjugates, termed the XRS Box, was synthesised to enable direct profiling across multiple aaRS targets, as described in Chapter 3. Several conjugates exhibited potent inhibition of their cognate P. falciparum aaRSs while maintaining selec- tivity over human homologues, with some demonstrating cross-species activity against other pathogens. Among these, the OSM-S-106–Pro conjugate (YNW69) emerged as a particularly promising candidate, exhibiting sub-nanomolar antiplasmodial potency, favourable pharmacokinetic properties, and strong target engagement of PfProRS, validated through biochemical, crystallographic, and protein translation inhibition assays, as detailed in Chapter 4. Chapter 5 concerns attempts to improve the synthesis of OSM-S-106 to support future analogue design. The borylation of a thienopyrimidine precursor is explored under Miyaura conditions on thienopyrimidine YNW4, which consistently produced deborylated and dimeric by-products. Comprehensive analysis by solution-phase NMR spectroscopy, LC-MS, and mechanistic controls confirmed the absence of the desired aryl–boronate product. These findings highlight the distinct reactivity of aminoth- ienopyrimidines and demonstrate the utility of real-time NMR in addressing synthetic challenges that need to be solved for an efficient approach towards future lead optimisation. Collectively, these studies advance the development of Series 3 compounds as openly accessible chemical leads, while extending the aaRS target space by establishing a panel of XRS Box chemical probes with potential broad-spectrum activity that are available to the community.

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