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Chemistry. 2017 Mar 23;23(17):4137-4148. doi: 10.1002/chem.201605231. Epub 2017 Feb 17.

Intramolecular Diaza-Diels-Alder Protocol: A New Diastereoselective and Modular One-Step Synthesis of Constrained Polycyclic Frameworks.

Author information

1
Sharjah Institute for Medical Research, University of Sharjah, P.O. Box 27272, Sharjah, UAE.
2
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA, 02114, USA.
3
Department of Immunology and Infectious Disease, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
4
Broad Institute of Harvard and, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.
5
Core Technologies Platform, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island, Abu Dhabi, UAE.
6
Department of Chemistry, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island, Abu Dhabi, UAE.
7
College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, UAE.

Abstract

Phenotype-based screening of diverse compound collections generated by privileged substructure-based diversity-oriented synthesis (pDOS) is considered one of the prominent approaches in the discovery of novel drug leads. However, one key challenge that remains is the development of efficient and modular synthetic routes toward the facile access of privileged small-molecule libraries with skeletal and stereochemical complexity and drug-like properties. In this regard, a novel and diverse one-pot procedure for the diastereoselective synthesis of privileged polycyclic benzopyrans and benzoxepines is described herein. These unexplored chemotypes were accessed by utilizing an acid-mediated diaza-Diels-Alder reaction of 2-allyloxy- and/or homoallyloxy benzaldehyde with 2-aminoazine building blocks. Profiling of representative analogues against blood-stage Plasmodium falciparum parasites identified three lead candidates with low micromolar antimalarial activity.

KEYWORDS:

antimalarial activity; cycloaddition; polycycles; structure-activity relationships; synthesis design

PMID:
27997727
DOI:
10.1002/chem.201605231

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