Synthesis and Characterization of Phenylalanine Amides Active against Mycobacterium abscessus and Other Mycobacteria

Abstract

Nα-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide [MMV688845, Pathogen Box; Medicines for Malaria Venture; IUPAC: (2R)-N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide)] is a hit compound, which shows activity against Mycobacterium abscessus (MIC90 6.25–12.5 μM) and other mycobacteria. This work describes derivatization of MMV688845 by introducing a thiomorpholine moiety and the preparation of the corresponding sulfones and sulfoxides. The molecular structures of three analogs are confirmed by X-ray crystallography. Conservation of the essential R configuration during synthesis is proven by chiral HPLC for an exemplary compound. All analogs were characterized in a MIC assay against M. abscessus, Mycobacterium intracellulare, Mycobacterium smegmatis, and Mycobacterium tuberculosis. The sulfone derivatives exhibit lower MIC90 values (M. abscessus: 0.78 μM), and the sulfoxides show higher aqueous solubility than the hit compound. The most potent derivatives possess bactericidal activity (99% inactivation of M. abscessus at 12.5 μM), while they are not cytotoxic against mammalian cell lines.

Broad-Spectrum In Vitro Activity of Nα-Aroyl-N-Aryl-Phenylalanine Amides against Non-Tuberculous Mycobacteria and Comparative Analysis of RNA Polymerases

“…The morpholine moiety was substituted by thiomorpholine sulfoxides and sulfones, which proved advantageous for the activity and solubility of the compound class, in addition to the exchange of the thiophene carboxylic acid amide to 2-fluorobenzoic acid amides. Compound 6 was included because it showed high activity while harbouring the hydroxyl group [25]. We also wanted to determine the influence of 5-fluoro substitution in para-position to the morpholine moiety (compounds 4 to 6).…”

“…The compounds selected for assessment against the strains described in this study were synthesized and characterized as described previously [25,32]. The selection of the test set considered their activity against previously tested mycobacteria, as well as diverse structural features that could affect the activity against different NTM species Compounds 1 to 7 were synthesized during a detailed SAR study that varied the ring systems of the chemical scaffold in the search for better activity against NTM.…”

“…The selection of the test set considered their activity against previously tested mycobacteria, as well as diverse structural features that could affect the activity against different NTM species Compounds 1 to 7 were synthesized during a detailed SAR study that varied the ring systems of the chemical scaffold in the search for better activity against NTM. The morpholine moiety was substituted by thiomorpholine sulfoxides and sulfones, which proved advantageous for the activity and solubility of the compound class, in addition to the exchange of the thiophene carboxylic acid amide to 2-fluorobenzoic acid amides Compound 6 was included because it showed high activity while harbouring the hydroxy group [25]. We also wanted to determine the influence of 5-fluoro substitution in paraposition to the morpholine moiety (compounds 4 to 6).…”

“…Nα-aroyl-N-aryl-phenylalanine amides (AAPs) represent a compound class that has displayed promising activity against Mtb and Mycobacterium abscessus [22][23][24], offering a potential avenue for novel therapeutic interventions against these challenging infections. Research exploring the medicinal chemistry [25][26][27] and antimycobacterial properties [28] of AAPs has shown encouraging results in vitro, demonstrating their ability to inhibit the growth of different mycobacterial species. This compound class's mechanism of action targets the essential mycobacterial RNA polymerase (RNAP) [29], disrupting key cellular processes and counteractions vital for their survival and propagation.…”

(3+2) Cycloaddition of Heteroaromatic N-Ylides with Sulfenes

“…Sulfones make up an important class of sulfur-containing molecules due to their plentiful applications in organic chemistry and medicinal chemistry . In particular, cyclic sulfones as well as sulfone-embedded N-heterocycles often serve as key pharmacophores in the design of a novel drug with improved physicochemical properties . Given the wide occurrence of N-fused heterocycles in pharmaceuticals, incorporating a sulfone functionality with N-fused heterocycles would provide attractive building blocks for the development of novel biologically active compounds and agrochemicals.…”