Escaping from Flatland: Antimalarial Activity of sp 3 -Rich Bridged Pyrrolidine Derivatives.

Autor:	Cox B; School of Life Sciences, University of Sussex, Brighton BN1 9QJ, U.K.; Photodiversity Ltd, c/o School of Life Sciences, University of Sussex, Brighton BN1 9QJ, U.K., Duffy J; Medicines for Malaria Venture, PO Box 1826, 20 Route de Pré-Bois, 1215 Geneva 15, Switzerland., Zdorichenko V; Photodiversity Ltd, c/o School of Life Sciences, University of Sussex, Brighton BN1 9QJ, U.K., Bellanger C; Photodiversity Ltd, c/o School of Life Sciences, University of Sussex, Brighton BN1 9QJ, U.K., Hurcum J; School of Life Sciences, University of Sussex, Brighton BN1 9QJ, U.K., Laleu B; Medicines for Malaria Venture, PO Box 1826, 20 Route de Pré-Bois, 1215 Geneva 15, Switzerland., Booker-Milburn KI; School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, U.K.; Photodiversity Ltd, c/o School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, U.K., Elliott LD; School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, U.K., Robertson-Ralph M; Photodiversity Ltd, c/o School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, U.K., Swain CJ; Cambridge MedChem Consulting, CB22 4RN Cambridge, U.K., Bishop SJ; Photodiversity Ltd, c/o School of Life Sciences, University of Sussex, Brighton BN1 9QJ, U.K., Hallyburton I; Drug Discovery Unit, Wellcome Centre for Anti-infective Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K., Anderson M; Drug Discovery Unit, Wellcome Centre for Anti-infective Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2020 Nov 10; Vol. 11 (12), pp. 2497-2503. Date of Electronic Publication: 2020 Nov 10 (Print Publication: 2020).
DOI:	10.1021/acsmedchemlett.0c00486
Abstrakt:	We utilized synthetic photochemistry to generate novel sp 3 -rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1-5 μM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound ( 9 ) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality. Competing Interests: The authors declare the following competing financial interest(s): B.C. and K.I.B.M. are employees of their respective universities and cofounders and owners of Photodiversity Ltd. J.D. and B.L. are employees of Medicines for Malaria Venture (MMV). (© 2020 American Chemical Society.)
Databáze:	MEDLINE
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