Synthesis, characterization and biological activities of hererocycles : peptides, O, N, and S based small molecules

Abstract

This study is based on the synthesis and characterization of quinoline based peptides and heterocycles containing oxygen, nitrogen and sulfur atoms by using new catalysts. In addition, the biological activities of the novel small molecules is evaluated. A total of 71 small molecules were prepared by using multi-component reactions including Ugi and Kabachnik-Fields reaction. The Ugi four-component reaction was implemented for the synthesis of medicinally important 13 new quinolinyl-lipoyl peptides (QLPs) and one quinolonyl-lipoyl peptide (QOLP) by microwave irradiation using methanol as medium. A series of 12 new quinolinyl-4H-pyrans (QPs), two quinolonyl-4H-pyrans (QOPs) and one indolyl-4H-pyran (IP) were successfully synthesized via a three-component reaction using ethanol as solvent in the presence of a new catalyst: humic acid supported 1-butyl- 3-methylimidazolium thiocyanate ionic liquid catalyst (HASIL) under microwave irradiation. By using Kabachnik-Fields reaction, a total of 14 novel α-aminobenzylthio- quinolinyl phosphonates (BTQPs) were synthesized in the presence of a catalytic amount of iron-loaded boron nitride (Fe/BN) catalyst by using water as medium. A series of 14 novel benzylthioquinolinyl-1,4-dihydropyridines (BTQ-DHPs) were synthesized with high yields in short reaction time by a four-component reaction in the presence of iodine- loaded boron nitride (I/BN) catalyst by using water as solvent. A total of 14 derivatives of 2-amino-4H-pyran-3-carbonitrile derivatives (APCs) were prepared by using calcium loaded boron nitride (Ca/BN) in ethanol as solvent. This transformation transpired via a Knoevenagel condensation, Michael addition and intra-molecular cyclization. The prepared catalysts: HASIL, Fe/BN, I/BN and Ca/BN were characterized by XRD, SEM with EDX, TEM, DSC, TGA, BET, Raman spectra and FTIR analysis. All the synthesized molecules (QLPs, QOLP, QPs, QOPs, IP, BTQPs, BTQ-DHPs and APCs) were confirmed by FTIR, 1H-NMR, 13C-NMR and elemental analysis. Moreover, 19F- NMR, 31P-NMR and TOF-MS analysis were included for some selected compounds. In every chapter, one model compound was selected and discussed with two-dimensional spectra such as HSQC, DEPT 90º, DEPT 135º (selected), COSY, NOESY and HMBC. Among the synthesized compounds, a total of 48 compounds (8 QLPs, 15 (QPs, QOPs and IP), 10 BTQPs, 10 BTQ-DHPs and 5 APCs) were subjected to antimicrobial activities with Bacillus cereus, Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Candida albicans and Candida utilis and antioxidant studies were observed by the radical scavenging assay. The toxicity studies were

evaluated using the brine shrimp assay and the mortality rate was noted. Among them, 4 peptides, 7 pyrans, 8 aminophosphonates, 7 dihydropyridines and 5 carbonitriles showed good antimicrobial activity whilst 3 peptides, 9 pyrans, 6 aminophosphonates and 4 dihydropyridines showed antioxidant potential. Also, 4 peptides, 5 pyrans, 8 aminophosphonates and 5 dihdyropyridines showed mortality rate less than 50 % upto 48 h. The molecular docking studies were performed by Libdock score with DNA gyrase, Mtb gyrase and Staphylococcus aureus gyrase. A docking score of 183.24 kcal/mol and 165.01 kcal/mol were recorded for 2 peptides compared to ciprofloxacin. Among quinolinyl pyrans, one QP showed higher binding affinity of 96.96 kcal/mol with Mtb DNA gyrase. One BTQP showed more potency towards Staphylococcus aureus gyrase with 149.97 kcal/mol and one BTQ-DHP showed a strong ligand-protein interaction toward Staphylococcus aureus gyrase with Libdock score of 125.27 kcal/mol. The advantages of the synthetic methodology of this project are its green approach, easy work up, mild reaction conditions, the use of an inexpensive solvent, short reaction times with higher yields and recyclability of the catalyst.