Synthesis of substituted N-(2'-nitrophenyl)pyrrolidine-2-carboxamides towards the design of proline-rich antimicrobial peptide mimics to eliminate bacterial resistance to antibiotics

Jocelyn A Odusami; Monisola I Ikhile; Josephat U Izunobi; Idris A Olasupo; Foluso O Osunsanmi; Andrew R Opoku; Marthe C D Fotsing; Olayinka T Asekun; Oluwole B Familoni; Derek T Ndinteh

doi:10.1016/j.bioorg.2020.104340

Synthesis of substituted N-(2'-nitrophenyl)pyrrolidine-2-carboxamides towards the design of proline-rich antimicrobial peptide mimics to eliminate bacterial resistance to antibiotics

Bioorg Chem. 2020 Dec:105:104340. doi: 10.1016/j.bioorg.2020.104340. Epub 2020 Oct 6.

Affiliations

¹ Department of Chemistry, University of Lagos, Akoka, Lagos, Nigeria; Department of Applied Chemistry, University of Johannesburg, Johannesburg, South Africa; Department of Chemical Sciences, Yaba College of Technology, Yaba, Lagos, Nigeria.
² Department of Applied Chemistry, University of Johannesburg, Johannesburg, South Africa. Electronic address: mikhile@uj.ac.za.
³ Department of Chemistry, University of Lagos, Akoka, Lagos, Nigeria.
⁴ Department of Biochemistry & Microbiology, University of Zululand, Kwadlangezwa, South Africa.
⁵ Department of Applied Chemistry, University of Johannesburg, Johannesburg, South Africa.
⁶ Department of Chemistry, University of Lagos, Akoka, Lagos, Nigeria. Electronic address: familonio@unilag.edu.ng.

PMID: 33096308
DOI: 10.1016/j.bioorg.2020.104340

Abstract

The treatment of diseases is under threat due to the increasing resistance of disease-causing bacteria to antibiotics. Likewise, free radical-induced oxidative stress has been implicated in several human disease conditions, such as cancer, stroke and diabetes. In the search for amino acid analogues with antibacterial and antioxidant properties as possible mimics of antimicrobial peptides, substituted N-(2'-nitrophenyl)pyrrolidine-2-carboxamides 4a-4k and N-(2'-nitrophenyl)piperidine-2-carboxamides 4l-4n have been synthesized via a two-step, one-pot amidation of the corresponding acids, using thionyl chloride with different amines in dichloromethane. The carboxamides were characterized by infrared and nuclear magnetic resonance spectroscopy, mass spectrometry and elemental analysis. Carboxamides 4a-4n were assayed against five Gram-positive and five Gram-negative bacterial strains using the broth micro-dilution procedure and compared to standard antibiotic drugs (streptomycin and nalidixic acid). 4b showed the highest antibacterial activity with a minimum inhibitory concentration (MIC) value of 15.6 µg/mL against Staphylococcus aureus. Pertinently, 4b and 4k are promising candidates for narrow-spectrum (Gram-positive) and broad-spectrum antibiotics, respectively. The antioxidant properties of the carboxamides were also evaluated using the 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical cation. 4a and 4k recorded the lowest IC₅₀ values of 1.22 × 10^-3 mg/mL (with DPPH) and 1.45 × 10^-4 mg/mL (with ABTS), respectively. Notably, 4k recorded about 2.5 times better antioxidant capacity than the positive controls - ascorbic acid and butylated hydroxyanisole. These results bode well for N-aryl carboxamides as good mimics and substitutes for antimicrobial peptides towards mitigating bacterial resistance to antibiotics as well as ameliorating oxidative stress-related diseases.

Keywords: Antibacterial; Antioxidant; Piperidine-2-carboxamides; Prolinamides; Structure–Activity Relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemistry*
Anti-Bacterial Agents / pharmacology
Antioxidants / chemical synthesis*
Antioxidants / pharmacology
Ascorbic Acid / pharmacology
Butylated Hydroxyanisole / pharmacology
Drug Design
Humans
Microbial Sensitivity Tests
Nalidixic Acid / pharmacology
Oxidative Stress / drug effects
Pore Forming Cytotoxic Proteins / chemical synthesis*
Pore Forming Cytotoxic Proteins / pharmacology
Proline / chemistry*
Pyrrolidines / chemical synthesis*
Pyrrolidines / pharmacology
Streptomycin / pharmacology
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Antioxidants
Pore Forming Cytotoxic Proteins
Pyrrolidines
Butylated Hydroxyanisole
Nalidixic Acid
Proline
Ascorbic Acid
Streptomycin