Polymorphism of an Nα-Aroyl-N-Aryl-Phenylalanine Amide: An X-ray and Electron Diffraction Study

Author:

Lang Markus1,Goddard Richard2ORCID,Patzer Michael2,Ganapathy Uday S.3,Dick Thomas345ORCID,Richter Adrian1ORCID,Seidel Rüdiger W.1ORCID

Affiliation:

1. Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle, Germany

2. Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany

3. Center for Discovery and Innovation, Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ 07110, USA

4. Department of Medical Sciences, Hackensack Meridian School of Medicine, 123 Metro Blvd, Nutley, NJ 07110, USA

5. Department of Microbiology and Immunology, Georgetown University, 3900 Reservoir Road N.W., Washington, DC 20007, USA

Abstract

In view of the rise of drug-resistant tuberculosis and difficult-to-treat related diseases caused by non-tuberculous mycobacteria, there is an urgent need for antimycobacterial drug discovery. Nα-aroyl-N-aryl-phenylalanine amides (AAPs) have been identified as antimycobacterial agents and are subject to lead optimization. The aim of the present study is to evaluate the impact of N-aryl ortho cyano substitution in a lead compound on the crystal and molecular structure and its in vitro activity against Mycobacterium abscessus. The title AAP can be conveniently synthesized from N-Boc-protected d-phenylalanine in two amide coupling steps using a previously established racemization-free method. Two polymorphic forms in the solid-state are described, as discovered by X-ray and electron diffraction. The introduction of a cyano group in the ortho position of the AAP N-aryl ring, however, leads to loss of in vitro activity against M. abscessus subsp. abscessus.

Funder

Deutsche Forschungsgemeinschaft

Mukoviszidose Institut gGmbH (Bonn, Germany) research

Publisher

MDPI AG

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