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

• Published in: Bioorganic chemistry 2020-12, Vol.105, p.104340, Article 104340
• Main Authors: Odusami, Jocelyn A., Ikhile, Monisola I., Izunobi, Josephat U., Olasupo, Idris A., Osunsanmi, Foluso O., Opoku, Andrew R., Fotsing, Marthe C.D., Asekun, Olayinka T., Familoni, Oluwole B., Ndinteh, Derek T.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Antioxidant; Antioxidants - chemical synthesis; Antioxidants - pharmacology; Ascorbic Acid - pharmacology; Butylated Hydroxyanisole - pharmacology; Drug Design; Humans; Microbial Sensitivity Tests; Nalidixic Acid - pharmacology; Oxidative Stress - drug effects; Piperidine-2-carboxamides; Pore Forming Cytotoxic Proteins - chemical synthesis; Pore Forming Cytotoxic Proteins - pharmacology; Prolinamides; Proline - chemistry; Pyrrolidines - chemical synthesis; Pyrrolidines - pharmacology; Streptomycin - pharmacology; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104340

[Display omitted] •New N-aryl cycloamino-2-carboxamides 4a–4n have been synthesized and characterized.•An SN2-type mechanism has been proposed and enumerated.•Carboxamide 4b gave a low MIC of 15.6 μg/mL against Gram-positive S. aureus.•Carboxamide 4k had 2.5 times better antioxidant capacity than ascorbic acid and BHA. 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.