Toward the Synthesis and Improved Biopotential of an N-methylated Analog of a Proline-Rich Cyclic Tetrapeptide from Marine Bacteria

Abstract

An N-methylated analog of a marine bacteria-derived natural proline-rich tetracyclopeptide was synthesized by coupling the deprotected dipeptide fragments Boc-l-prolyl-l-N-methylleucine-OH and l-prolyl-l-N-methylphenylalanine-OMe. A coupling reaction was accomplished utilizing N,N′-Dicyclohexylcarbodidimde (DCC) and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC·HCl) as coupling agents and Triethylamine (TEA) or N-methylmorpholine (NMM) as the base in the presence of the racemization suppressing agent. This was followed by the cyclization of the linear tetrapeptide fragment under alkaline conditions. The structure of the synthesized cyclooligopeptide was confirmed using quantitative elemental analysis, FTIR (Fourier-transform infrared spectroscopy), 1H NMR (Nuclear magnetic resonance spectroscopy), 13C NMR, and mass spectrometry. From the bioactivity results, it was clear that the newly synthesized proline-rich tetracyclopeptide exhibited better anthelmintic potential against Megascoplex konkanensis, Pontoscotex corethruses, and Eudrilus eugeniae at a concentration of 2 mg/mL as well as improved antifungal activity against pathogenic dermatophytes Trichophyton mentagrophytes and Microsporum audouinii at a concentration of 6 μg/mL, as compared to non-methylated tetracyclopeptide. Moreover, N-methylated tetracyclopeptide displayed significant activity against pathogenic Candida albicans.

Synthesis and Insecticidal Evaluation of Chiral Neonicotinoids Analogs: The Laurel Wilt Case

“…Likewise, its larvicidal activity was severely decreased when the substituent on the benzene ring was changed from position four to position two or three. However, the improved biopotential of the N -methylated compounds studied in our work is in agreement with Dahiya et al [ 19 ], who synthesized an N -methylated analog of a proline-rich cyclic tetracyclopeptide from marine bacteria with enhanced anthelmintic and antifungal activity, compared to the non-methylated tetracyclopeptide. Cyclic compounds showed up to 67% mortality for compound 36 and 47% mortality for compound 35 ( Figure 5 ).…”

Strategies in Translating the Therapeutic Potentials of Host Defense Peptides

“…A range of N-and C-terminal modification strategies have been proposed to enhance the antimicrobial efficacy and/or cell selectivity of natural and synthetic HDPs (102,136,137). Amongst all, N-terminal acetylation (CH 3 CO-) and Cterminal amidation (-NH 2 ) are the two most commonly attempted strategies (102).…”

Natural Bioactive Thiazole-Based Peptides from Marine Resources: Structural and Pharmacological Aspects

“…Despite of lot of challenges associated with synthesizing complex peptide molecules [132][133][134][135], syntheses of diverse aromatic/heteroaromatic peptides were accomplished by several research groups employing diverse techniques of peptide synthesis including solid-phase peptide synthesis (SPPS), liquid-phase peptide synthesis (LPPS), and a mixed solid-phase/solution synthesis strategy, irrespective of whether these congeners belong to linear analogues [136][137][138][139][140][141][142][143][144][145][146][147][148][149][150][151] or are cyclic in nature [152][153][154][155][156][157][158][159][160][161][162][163][164][165][166][167][168][169]. Literature is enriched with reports involving synthesis of various heterocyclic cyclopolypeptides bearing thiazole/thiazoline/tryptophan/histidine moieties viz.…”