Synthesis, and docking studies of novel heterocycles incorporating the indazolylthiazole moiety as antimicrobial and anticancer agents

Abdallah E Abdallah,Nadia T A Dawoud,Doaa R Lotfy,Hamada El-Gendi,Esmail M El-Fakharany

doi:10.1038/s41598-022-07456-1

Abdallah E Abdallah, Nadia T A Dawoud + Show 3 more

Open Access

https://doi.org/10.1038/s41598-022-07456-1

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Abstract

The current study was directed toward developing a new series of fused heterocycles incorporating indazolylthiazole moiety. The newly synthesized compounds were characterized through elemental analysis and spectral data (IR, 1H-NMR, 13C-NMR, and Mass Spectrometry). The cytotoxic effect of the newly synthesized compounds was evaluated against normal human cells (HFB-4) and cancer cell lines (HepG-2 and Caco-2). Among the synthesized compounds, derivatives 4, and 6 revealed a significant selective antitumor activity, in a dose-dependent manner, against both HepG-2 and Caco-2 cell lines, with lower risk toward HFB-4 cells (normal cells). Derivative 8 revealed the maximum antitumor activity toward both tumor cell lines, with an SI value of about 26 and IC50 value of about 5.9 μg/mL. The effect of these derivatives (8, 4, and 6) upon the expression of 5 tumor regulating genes was studied through quantitative real-time PCR, where its interaction with these genes was simulated through the molecular docking study. Furthermore, the antimicrobial activity results revealed that compounds 2, 7, 8, and 9 have a potential antimicrobial activity, with maximum broad-spectrum activity through compound 3 against the three tested pathogens: Streptococcus mutans, Pseudomonas aeruginosa, and Candida albicans. The newly prepared compounds also revealed anti-biofilm formation activity with maximum activity against Streptococcus mutans, Pseudomonas aeruginosa, and Candida albicans, respectively.

Highlights

The current study was directed toward developing a new series of fused heterocycles incorporating indazolylthiazole moiety
Our findings indicated that the synthesized derivative 8 showed superior antitumor activity toward both tested tumor cells indicated with an selectivity index (SI) value of approximately 26, with very high selectivity toward tumor cells, as the IC50 values were nearly 5.9 μg/mL toward both HepG-2 and Caco-2 cell lines
The newly prepared compounds revealed low to medium antifungal activity against Candida albicans with a maximum antifungal activity through compound 3 (MIC of 40.74 μg/mL), representing 36% clotrimazole activity

Summary

Introduction

The current study was directed toward developing a new series of fused heterocycles incorporating indazolylthiazole moiety. Heterocyclic derivatives, which contain at least two different elements, have received a great deal of attention in the development of pharmacologically active molecules and advanced organic materials[13,14] and account for more than 75% of the materials currently used clinically[15]. Due to their broad biological and pharmacological applications, Sulfur, nitrogen, and/or oxygen-containing heterocyclic compounds such as thiophene and pyrazole are always of interest to medicinal chemists and r esearchers[16–18]. According to the preceding information, the present study concerns the synthesis and characterization of novel furan, thiophene, pyrazole, pyran, and pyridine derivatives from indazolylthiazolidinone moieties Their biological potential, including anti-tumor and anti-microbial activities, was evaluated

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