Novel C3-Methylene-Bridged Indole Derivatives with and without Substituents at N1: The Influence of Substituents on Their Hemolytic, Cytoprotective, and Antimicrobial Activity.

Alkaloids are natural compounds useful as scaffolds for discovering new bioactive molecules. This study utilized alkaloid gramine to synthesize two groups of C3-substituted indole derivatives, which were either functionalized at N1 or not. The compounds were characterized by spectroscopic methods. The protective effects of the new compounds against in vitro oxidative hemolysis induced by standard oxidant 2,2'-azobis(2-amidinopropane dihydro chloride (AAPH) on human erythrocytes as a cell model were investigated. Additionally, the compounds were screened for antimicrobial activity. The results indicated that most of the indole derivatives devoid of the N1 substitution exhibited strong cytoprotective properties. The docking studies supported the affinities of selected indole-based ligands as potential antioxidants. Furthermore, the derivatives obtained exhibited potent fungicidal properties. The structures of the eight derivatives possessing indole moiety bridged to the imidazole-, benzimidazole-, thiazole-, benzothiazole-, and 5-methylbenzothiazoline-2-thiones were determined by X-ray diffraction. The C=S bond lengths in the thioamide fragment pointed to the involvement of zwitterionic structures of varying contribution. The predominance of zwitterionic mesomers may explain the lack of cytoprotective properties, while steric effects, which limit multiple the hydrogen-bond acceptor properties of a thione sulfur, seem to be responsible for the high hemolytic activity.

Synthesis and Hemolytic Activity of Bile Acid-Indole Bioconjugates Linked by Triazole.

New formyl and acetyl derivatives of bile acid propargyl esters and their bioconjugates with modified gramine molecules have been obtained using the click chemistry method to study their hemolytic potency. The structures of all compounds were confirmed by spectral (1H- and 13C NMR and FT-IR) analysis and mass spectrometry (ESI-MS) as well as PM5 semiempirical methods. According to the results, the structural modification of formyl and acetyl bile acid derivatives, leading to the formation of new propargyl esters and indole bioconjugates, reduces their hemolytic activity. According to molecular docking studies, the tested ligands are highly likely to exhibit a similar affinity, as native ligands, for the active sites of specific protein domains (PDB IDs: 2Q85 and 5V5Z). The obtained results may be helpful for the development of selective bile acid bioconjugates as effective antibacterial, antifungal, or antioxidant agents.

Novel gramine-based bioconjugates obtained by click chemistry as cytoprotective compounds and potent antibacterial and antifungal agents.

A series of indole-1,4-disubstituted-1,2,3-triazole conjugates were synthesised by click chemistry. The haemolytic properties and cytoprotective activity of all the newly synthesised indole-triazole conjugates were tested in vitro. In addition, molecular docking was performed in silico for the selected conjugates to determine their antibacterial and antifungal properties. The results indicate that indole-triazole derivatives effectively protect human erythrocytes against free radical-induced haemolysis in a structure-dependent manner and that bis-indole-bis-triazole derivatives with alkyl linkers are excellent cytoprotective agents against oxidative haemolysis. The tested series of indole-1,4-disubstituted-1,2,3-triazole conjugates may have an affinity for the active sites of specific protein domains (PDB IDs: 2Q85 and 5V5Z) according to molecular docking studies.