g Open Source Malaria Meeting #9 Nov 24 th 2014 Location:Agenda: g 1.1 From Last Time: Latest Single-point Data from GSK g 1.1 From Last Time: Latest Single-point Data from GSK g 1.1 IC 50 Values for the GSK-Active Compounds g 1.2 Potencies of Latest Compounds Sent to Syngene g 1.2 Trends in Latest Data g 1.3 Data from Lawrence University/Kip Guy (Series 1a) g 2.1 Access to Core Ether and Amide Triazolopyrazines Jo Ubels Tom Macdonald g 2.2 Access to Halogenated Triazolopyrazine Core Tom Macdonald g 2.3 Access to Fluoroalkene Isostere and Aminocarbonylation Chemistry Tom Macdonald Jo Ubels g 2.4/2.5 Racemic/Enantioenriched MMV669844 g 2.6 Edinburgh Syntheses in Series 3 g 2.7 Inputs from Sydney Grammar School g 3.1 hERG Data from AstraZeneca Scott Obach, Christine Orozco 3.2 Pfizer AO Assay Substitution with Cl retains potency, but at what cost? Likely AO substrate, given Cl is EWG 3.2 Position-8 Variants Revisited / AO Metabolites Metabolites unlikely to be active No activity in all cases 3.3 Ion Homeostasis Assay on Series 1 and 3 (Kirk) Compounds sent, awaiting data 3.4 Evaluation of Series 4 vs ATP4 Resistant Mutants 4.1 ATP4/Malaria Box (Kirk) A. M. Lehane, M. C. Ridgway, E. Baker and K. Kirk, Molec. Microbiol. 2014, 94, 327339. DOI: /mmi.12765 g 5. Key Scientific Advice from the ESAC Aim for log P between 1.5 and 3.5 Use predictive tools such as MetaSite for predicting sites of metabolism, vs knowns Revisit other cores with good metabolic profiles, e.g. MMV Use more sp3 carbons, and de-planarize through chirality at C-5 or in substitutions at C-2 or C-5 Use more heteroaryls, or saturated groups. Additional chemical biology approaches to MoA: mutants, ko, kd, pull down Need major website restructure to appeal to newcomers - more on that later. 5 Whats Next? 6/7 Pubs/Publicity 8/9/10 AOB/Next Meeting? LEGACY SLIDES FOLLOW g Chiral Ether Compounds Analytical separation by HPLC = difficult due to insolubility of compound Appeal for help may be necessary Racemic Synthesis Enantioselective Synthesis HPLC Assay Problems with base g Remaining Series 3 compounds https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/161 g Planning: Replacement of Triazole Phenyl Substituent g Planning: Previous Suggestions: Sabin, November 2013 https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/101 g Planning: Previous Suggestions: Joie Garfunkel, October 2013