Synthesis and biological activity studies of some novel indole ring-linked thiazolidone hybrid molecules

Abba, A. Synthesis and Biological Activity Studies of Some Novel Indole Ring Linked Thiazolidone Hybrid Molecules Yeditepe University Institute of Health Science, PhD Thesis on Pharmaceutical Chemistry Programme, İstanbul, 2024. The purposes of this study were the synthesis, characterization, biological activities and in silico ADME studies of novel indole-thiazolidin-4-one hybrid compounds. In this study, (2E/Z,5E/Z)-5-(substituted) benzylidene-2-{[2-(3H-indol-3-yl)ethyl]imino}-3-phenyl-1,3-thiazolidin-4-one derivatives were synthesized through 3 steps protocol. In the first step, 1-(2-(indole-3-yl) ethyl)-3-phenylthiourea (I) was synthesized by dissolving phenylisothiocyanate in toluene and combined with tryptamine at room temperature for 2 hours. In the second step, compound I was dissolved in ethanol and followed by the addition of anhydrous sodium acetate, the mixture was kept in cold medium in order to introduce chloroacetyl chloride and refluxed for 12 hours to produce (2E/Z)-2-{[2-(3H-indol-3-yl)ethyl]imino}-3-phenyl-1,3-thiazolidin-4-one (II). Finally, product (II) was dissolved in ethanol and followed by the addition piperidine as base and the desired derivative of aromatic aldehydes and refluxed 30 minutes in order to obtaine twenty four novel derivatives of the final form of product (III) (2E/Z,5E/Z)-5-(substituted) benzylidene-2-{[2-(3H-indol-3-yl)ethyl]imino}-3-phenyl-1,3-thiazolidin-4-one. Structure identification of the synthesized compounds was done by spectral methods such as IR, 1H NMR, 13C NMR and LC/Q-TOF Spectrum methods. The anti-microbial activity of compounds 1-24 was assessed using the disc diffusion method. Compounds were subjected to testing against Enterococcus hirae ATCC 10541, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 10536, Acinetobacter baumannii ATCC 19606, Pseudomonas aeruginosa ATCC 15442, and Candida albicans ATCC 10231. The synthesized compounds showed moderate activity in general against the tested microorganism. The highest anti-bacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli compounds 4, 8, 10, 11, 12, 14, 19, 21 and 24 gave the highest inhibition zone of 18 mm. While the highest anti-fungal activity against C. albicans was observed through compounds 4, 8, 10, 11, 12, 14, 19, 21, 24 as the best in terms of the inhibition zone by having a diameter of 15 mm. Also, agar dilution method for MICs determination of antimicrobial activity of these compounds was tested against Enterococcus hirae ATCC 10541, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 11229, Acinetobacter baumannii ATCC 19606, Pseudomonas aeruginosa ATCC 15442 and Candida albicans ATCC 10231 microorganisms. The minimum inhibitory concentration of the compounds 4, 8, 10, 11,12, 14, 19, 21 and 24 against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and C. albicans were 25 μg/mL. On the other hand, the synthesized compounds (1-24) demonstrated their cytotoxic effects on breast cancer cell line (MCF-7), non-tumorigenic mammary epithelial cells (MCF12A), Human Umbilical Vein Endothelial Cell (HUVEC), adenocarcinomic human alveolar basal epithelial cells (A549) and human prostate cancer cell line (PC3). The tested compounds showed excellent to moderate cytotoxic activity according to their pharmacophore moiety. The compounds 8, 10, 15, 21 and 23 showed the highest activities in terms of minimum inhibitory effect and selectivity. For that, they were selected for their tubulin polymerization inhibitory activity, where they showed vinblastine-like activity in inhibiting the tubulin polymerization for 20 minutes. Within the scope of in-silico studies, the values of the synthesized compounds were tested for their ability in hydrogen bonding formation, the partition coefficient between n-octanol and water (log Po/w), Water Solubility (log S), pharmacokinetics and skin permeability (log Kp) regarding absorption, distribution, metabolism and elimination properties (ADME) were calculated using the SwissADME module. The below structure shows the general formula of synthesized compounds. R: H, 4-nitro, 4-chloro, 3-methyl, 3-methoxy, 2-ethyl, 2-methyl, 4-hydroxy, 3-fluoro, 3-ethoxy-4-hydroxy, 2-methoxy, 2,4-dimethoxy, 4-bromo, 4-fluoro, 3-hydroxy-4-methoxy, 2,3-dimethyl, 2-bromo, 3-bromo-4-hydroxy , 2,5-dimethyl, 3,5-dibromo-4-hydroxy, 3,4-dimethyl, 2,4,5-trimethoxy, 3,5-dichloro, and 2,5-dichloro. Keywords: Indole, Thizaolidin-4-one, Antimicrobial, Anticancer, cytotoxicity, Tubulin, Tubulin Polymerization Inhibitors, Vinblastine.