Synthesis, molecular docking, and molecular dynamic simulation studies of new 1,3,4-thiadiazole derivatives as potential apoptosis inducers in A549 lung cancer cell line

Abstract

1,3,4-Thiadiazoles are structures that are bioisosteres of 1,3,4-oxadiazole and pyrimidine ring, which are found in the structure of many drugs and anticancer active newly studied derivatives. In the past, high effect profiles have been observed in many molecules created, based on the anticancer effects of the 2-amino-1,3,4-thiadiazole (NSC 4728) molecule and acetazolamide molecules. Focusing on these molecules and evaluating them in terms of mechanistic effects, twelve new N-[5-((3,5-dichlorophenoxy) methyl]-1,3,4-thiadiazole derivatives (3a–3i) were synthesized and their biological activities were investigated in lung cancer cells. The anticancer effects of the compounds were evaluated on the A549 and L929 cell lines. Compound 3f, namely 2-[(5-chlorobenzotiyazol-2-yl)thio]-N-[5-[(3,5-dichlorophenoxy)methyl]-1,3,4-thiadiazol-2-yl]acetamide, showed better activity than cisplatin, exhibiting high inhibitory potency (IC₅₀: <0.98 μg/mL) and selectivity against A549 cell line even at the lowest concentration tested. Compounds 3c, 3f, and 3h with the lowest IC₅₀ values of the compounds exhibited an excellent percentage of apoptosis between 72.48 and 91.95% compared to cisplatin. The caspase-3 activation and mitochondrial membrane potential change of the aforementioned three compounds were also studied. Moreover, matrix metalloproteinase-9 (MMP-9) inhibition potential of all final compounds was also investigated and IC₅₀ values for compounds 3b and 3g were identified as 154.23 and 107.28 µM. Molecular docking and molecular dynamic simulation studies for MMP-9 enzyme inhibition were realized on these compounds and the nitrogen atoms of amide and thiadiazole moieties’ ascertained that they play a key role in chelating with Zn metal, at the same time, (thio)ether moieties allow conformational change resulting in the ligand can make more stable contacts.

Communicated by Ramaswamy H. Sarma

Keywords:

• Thiadiazole
• cytotoxicity
• apoptosis
• caspase-3 activation
• matrix metalloproteinase-9 inhibition
• molecular docking
• molecular dynamic simulation

Acknowledgments

The authors would like to express their gratitude for the use and benefit of the methods in their previous work under the identity (Yurttaş et al., 2020).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by the Anadolu University Scientific Research Project, Eskisehir, Turkey (Project no. 1905S029).