PHE-GLY DIPEPTIDE CARBOXAMIDE SULPHONAMIDES: SYNTHESIS, ELUCIDATION, IN-VITRO AND IN-SILICO ACTIVITIES.

Abstract

The combination of sulfonamide, carboxamide, dipeptide and amino groups in a drug candidate is a doorway to compounds with exciting biological activities. The synthesis of three new arylsulphonamoyl Phe-Gly dipeptide carboxamides is reported herein. Three benzenesulphonamide intermediates (8a-c) were prepared by reacting benzenesulphonylchloride, 4-nitrobenzenesulphonylchloride, and 4-methylbenzenesulphonylchloride with L-phenylalanine (7a-c). The amino protection agent Boc anhydride was used with 1, 4-dioxane to protect the amino group of glycine to form Boc-glycine 2. The reaction of 4-nitroaniline 3 with Boc-protected glycine yielded Boc-protected carboxamide 4. The amine deprotection agents DCM/TFA (1:1) were used to produce product 5. The reaction of the intermediates (8a-c) with the deprotected carboxamide produced the Phe-Gly dipeptide target molecules (9a-c). The structures were confirmed by FTIR, 1H-NMR and 13C NMR. Computational investigations were performed to ascertain their antibacterial and antifungal potentials. All compounds showed good binding. The binding energies (kcal/mol) for antibacterial and antifungal activities -7.0 to -7.6 and -8.1 to 10.1 respectively. Antimicrobial studies were conducted to ascertain the potencies of the compounds against two Gram positive bacteria (Staphylococcus aureus and Streptococcus pyogene), two Gram negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and Candida albicans. The inhibitory zone diameter (IZD) values were 2-40 mm. The MIC values in (mg/m) were 1.585 – 7.586 and the MBC values (mg/m) were 12.500 - 25.500. The compounds showed the highest activities toward Streptococcus pyogene and Escherichia coli. Computational studies were also conducted to determine the binding energies of the proteins in interaction with (1U1Z), (2W9S), (4KT6), (4X08), and (4YDE). The binding energies were in the range -5.6 to -10.1. The predicted hepatoxicity, carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity of the compounds also showed that they are good drug candidates