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Racemization-free synthesis of Nα-2-thiophenoyl-phenylalanine-2-morpholinoanilide enantiomers and their antimycobacterial activity.

ABSTRACT: Nα-2-thiophenoyl-D-phenylalanine-2-morpholinoanilide (MMV688845, IUPAC: N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide) from the Pathogen Box^® library (Medicines for Malaria Ventures, MMV) is a promising lead compound for antimycobacterial drug development. Two straightforward synthetic routes to the title compound starting from phenylalanine or its Boc-protected derivative are reported. Employing Boc-phenylalanine as starting material and the T3P^® and PyBOP^® amide coupling reagents enables racemization-free synthesis, avoiding the need for subsequent separation of the enantiomers. The crystal structure of the racemic counterpart gives insight into the molecular structure and hydrogen bonding interactions in the solid state. The R-enantiomer of the title compound (derived from D-phenylalanine) exhibits activity against non-pathogenic and pathogenic mycobacterial strains, whereas the S-enantiomer is inactive. Neither of the enantiomers and the racemate of the title compound shows cytotoxicity against various mammalian cells.

SUBMITTER: Mann L

PROVIDER: S-EPMC8325651 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Racemization-free synthesis of Nα-2-thiophenoyl-phenylalanine-2-morpholinoanilide enantiomers and their antimycobacterial activity.

Mann Lea L Lang Markus M Schulze Philipp P Halz Jan Henrik JH Csuk René R Hoenke Sophie S Seidel Rüdiger W RW Richter Adrian A

Amino acids 20210714 8

Nα-2-thiophenoyl-D-phenylalanine-2-morpholinoanilide (MMV688845, IUPAC: N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide) from the Pathogen Box<sup>®</sup> library (Medicines for Malaria Ventures, MMV) is a promising lead compound for antimycobacterial drug development. Two straightforward synthetic routes to the title compound starting from phenylalanine or its Boc-protected derivative are reported. Employing Boc-phenylalanine as starting material and the T3P<s ...[more]

PMID: 34259925

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Project description:The appearance of drug-resistant strains of Mycobacterium tuberculosis and the dramatic increase in infection rates worldwide evidences the urgency of developing new and effective compounds for treating tuberculosis. Benzimidazoles represent one possible source of new compounds given that antimycobacterial activity has already been documented for some derivatives, such as those bearing electron-withdrawing groups. The aim of this study was to synthesize two series of benzimidazoles, di- and trisubstituted derivatives, and evaluate their antimycobacterial activity. Accordingly, 5a and 5b were synthesized from hydroxymoyl halides 3a and 3b, and nitro-substituted o-phenylenediamine 4. Compound 11 was synthesized from an aromatic nitro compound, 4-chloro-1,2-phenylenediamine 9, mixed with 3-nitrobenzaldehyde 10, and bentonite clay. Although the synthesis of 11 has already been reported, its antimycobacterial activity is herein examined for the first time. 1,2,5-trisubstituted benzimidazoles 7a, 7b, and 12 were obtained from N-alkylation of 5a, 5b, and 11. All benzimidazole derivatives were characterized by FT-IR, NMR, and HR-MS, and then screened for their in vitro antimycobacterial effect against the M. tuberculosis H37Rv strain. The N-alkylated molecules (7a, 7b, and 12) generated very limited in vitro inhibition of mycobacterial growth. The benzimidazoles (5a, 5b, and 11) showed in vitro potency against mycobacteria, reflected in minimal inhibitory concentration (MIC) values in the range of 6.25-25 μg/mL. Consequently, only the 2,5-disubstituted benzimidazoles were assessed for biological activity on mouse macrophages infected with M. tuberculosis. A good effect was found for the three compounds. The cytotoxicity assay revealed very low toxicity for all the test compounds against the macrophage cell line. According to the docking study, 2,5-disubstituted benzimidazoles exhibit high affinity for an interdomain cleft that plays a key role in the GTP-dependent polymerization of the filamentous temperature-sensitive Z (FtsZ) protein. The ability of different benzimidazoles to impede FtsZ polymerization is reportedly related to their antimycobacterial activity. On the other hand, the 1,2,5-trisubstituted benzimidazoles docked to the N-terminal of the protein, close to the GTP binding domain, and did not show strong binding energies. Overall, 5a, 5b, and 11 proved to be good candidates for in vivo testing to determine their potential for treating tuberculosis.

Dataset Information

Racemization-free synthesis of Nα-2-thiophenoyl-phenylalanine-2-morpholinoanilide enantiomers and their antimycobacterial activity.

Publications

Racemization-free synthesis of Nα-2-thiophenoyl-phenylalanine-2-morpholinoanilide enantiomers and their antimycobacterial activity.

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