PowerPoint Presentation Malaria Libre 6th Project Meeting 18th December 2020 Agenda • Feedback of ESAC review • Status of action items from last meeting • Project update • Discussion – Medicinal Chemistry, Mechanism of action studies plan • How to contribute- new members? 2 Action items Feedback of ESAC review Keep a check on the novelty of scaffolds being worked upon and incorporate any learnings. [...] DGFA results on slide 6 Screening in STPH resistant panel STPH Results on slide 11 4 Discussion points Mechanism of action studies Way forward based on PRR results Challenges in synthesis of ongoing targets New proposals QSAR of aryl imidazole scaffold – update Comments on data representation on MMV webpages AOB 5 Profile of front runners Compound MMV 1803899 MMV1804508 MMCVo8nf9id2e8n8t1ial Pf po. [...] 2016, 81, 1269−1276 Proposed Strategy – Aryl imidazole • Design and synthesis of compounds to - Improve potency 3D7 IC50<100nM while reducing log D ≤ 4; fill in the SAR gaps - Improve metabolic stability by reducing log D and/or blocking putative metabolic hot spots • Generate invitro met ID of MMV892881 – volunteers? • Evaluate exemplars from to understand TCP4 & TCP 5 potential – Q1 2021 • Initi. [...] falciparum 3D7 Aim: Use untargeted metabolomics, proteomics and CETSA to determine the mode of action of the aryl piperazine and aryl imidazole scaffolds from the Malaria Libre program Metabolomics and proteomics methodological details: ▪ Test compounds: active and inactive analogues ▪ Compound concentration: 1 µM ▪ Incubation time: 5 hours ▪ Metabolite extraction: Cold methanol ▪ Protein solubili. [...] Sanjay 30 Ways of contribution • Design and synthesis of compounds to achieve the objectives • Synthesis of compounds • Carry out experimental in vitro Met ID • Screen front runners in lab derived strains other than 3D7; asexual intraerythrocytic blood stage assays, mechanism of action Details of objectives and plans: libre-data-repository 31 htt.
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