Synthesis, biological evaluation, and molecular docking studies of 1,3,4-thiadiazol-2-amide derivatives as novel anticancer agents

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Abstract

A series of 1,3,4-thiadiazol-2-amide derivatives (5a5y) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and FAK inhibitors. Among all the compounds, 5h showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC50 values of 0.45 and 0.31 μM, respectively. Compound 5h also exhibited significant FAK inhibitory activity (IC50 = 5.32 μM). Docking simulation was performed to position compound 5h into the FAK structure active site to determine the probable binding model. The results of antiproliferative and Western-blot assay demonstrated that compound 5h possessed good antiproliferative activity. Therefore, compound 5h with potent FAK inhibitory activity may be a potential anticancer agent.

Graphical abstract

A series of 1,3,4-thiadiazol-2-amide derivatives have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and FAK inhibitors. Compound 5h possessed the most potent FAK inhibitory activity (IC50 = 5.32 μM) and anticancer activities (IC50 = 0.45 μM for MCF-7 and IC50 = 0.31 μM for B16-F10). Docking simulation was performed to insert compound 5h into the crystal structure of FAK to determine the probable binding model.

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Introduction

Cancer is a class of diseases in which cell, or a group of cells display uncontrolled growth, invasion, and sometimes metastasis. During the last few decades, anticancer therapy has progressed significantly, but the management of malignancies in humans still constitutes a major challenge for contemporary medicine.1, 2, 3, 4

Focal adhesion kinase (FAK) was first discovered in 1992 and was implicated in integrin signaling.5, 6, 7 It is a 125 kDa protein tyrosine kinase recruited at an early stage to focal adhesions and is phosphorylated in response to cell attachment and mediates focal adhesion formation.8, 9 Focal adhesions are found at the cell membrane where the cytoskeleton interacts with the proteins of the extra-cellular matrix. The clustering of integrins at these sites attracts a large complex of proteins which regulate processes such as anchorage-dependent proliferation and cell migration. Signal transduction mediated by interactions between cells and the extracellular matrix (ECM) at focal adhesions is an important determinant of cell fate. Focal adhesion kinase is involved in multiple cellular functions such as cell proliferation, survival, motility, invasion, metastasis, and angiogenesis.10 Different approaches to inhibit FAK with FAK antisense oligonucleotides,11 dominant-negative C-terminal domain of FAK, FAK-CD or FRNK12, 13 or FAK siRNA,14, 15 caused decreased cellular viability, growth inhibition, or apoptosis. Recently, FAK was proposed to be a new potential therapeutic target in cancer.16, 17

Phenyl-1,3,4-thiadiazoles are a class of small molecules that have received much interest in the fields of chemistry and biology due to their broad spectrum of activity. The 1,3,4-thiadiazole scaffold is an interesting building block that has been used to synthesize a variety of useful bioactive compounds. Phenyl-1,3,4-thiadiazole derivatives have been reported to be anticancer,18 antimicrobial,19 anti-tubercular,20 anti-convulsant,21 anti-inflammatory,22 analgesic,22 anti-anxiety, anti-depressant23 and anti-viral24 agents. For this type of derivatives, a different mechanism of action is assigned, depending on the type of modification of 1,3,4-thiadiazole ring.25, 26, 27 The action connected with the apoptotic mechanisms and angiogenesis, which is a crucial step in the tumorigenesis, seems to be very promising in anticancer therapy.28, 29

In our previous publication we described synthesis and in vitro antiproliferative activity against some human cancer cell lines of compounds of 1,3,4-thiadiazole derivatives containing 1,4-benzodioxan.30 The significantly antiproliferative and FAK inhibitory effect of 1,3,4-thiadiazole derivatives were found.

As you know, amide derivatives were associated with broad spectrum of biological activities including antitumor properties.31 Herein, in continuation to extend our research on antitumor compounds with FAK structure inhibitory activity, we report in the present work the synthesis and structure–activity relationships of a series of 1,3,4-thiadiazol-2-amide derivatives as antitumor agents. Biological evaluation indicated that some of the synthesized compounds were potent inhibitors of FAK.

Section snippets

Chemistry

The synthetic route of the 1,3,4-thiadiazol-2-amide derivatives 5a5y is outlined in Scheme 1. These compounds were synthesized from 2-amino-1,3,4-thiadiazoles 3 and different substituted carboxylic acids 4. Firstly, the different substituted benzoic acid 1 were treated with thiosemicarbazide 2 in presence of phosphoryl chloride yielded 2-amino-1,3,4-thiadiazoles. Secondly, the coupling reaction between the obtained different substituted 2-amino-1,3,4-thiadiazoles and different substituted

Conclusion

In this study, a series of 1,3,4-thiadiazol-2-amide derivatives have been synthesized and evaluated for their antitumor activities. These compounds exhibited potent antiproliferative activities against MCF-7 and B16-F10 cells and FAK inhibitory activities. Among all of the compounds, 5h showed the most potent inhibition activity which inhibited the growth of MCF-7 and B16-F10 cell lines with IC50 values of 0.45 and 0.31 μM, respectively and inhibited the FAK with IC50 of 5.32 μM. Molecular

Materials and measurements

All chemicals and reagents used in the current study were of analytical grade. All the 1H NMR spectra were recorded on a Bruker DPX300 model Spectrometer in DMSO-d6 and chemical shifts were reported in ppm (δ). ESI-MS spectra were recorded on a Mariner System 5304 Mass spectrometer. Elemental analyses were performed on a CHN-O-Rapid instrument. TLC was performed on the glassbacked silica gel sheets (Silica Gel 60 GF254) and visualized in UV light (254 nm). Column chromatography was performed

Acknowledgements

The work was financed by National Natural Science Foundation of China (No. J1103512).

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