Design, Synthesis, Molecular Docking, and Biological Evaluation of Pyrazole 1-Carbothiamide Incorporated Isoxazole Derivatives

Abstract

Objectives: Novel isoxazole incorporated pyrazole carbothiamide 5 (a-r) was designed and synthesized, docked and evaluated for anticancer activity Michigan Cancer Foundation-7 (MCF-7), and breast cancer cell lines.
 Materials and Methods: Designed compounds were synthesized by the condensation of 1-(5-methyl-3-(4-nitrophenyl) isoxazole-4-yl) -3-(substitutedphenyl) prop-2-en-1-one (4) with thiosemicarbazides and substituted thiosemicarbazides to give the target molecules 5 (a-r). To predict the affinity and activity of the ligand molecule, the docking program Accelrys Discovery Studio 2.1 was employed to generate different bioactive binding poses of designing molecules at the active site of human Dihydrofolate Reductase (DHFR) (PDB ID: 1KMS). All the synthesized compounds were characterized based on the spectral and elemental analysis data. Antiproliferative activity was performed against MCF-7 breast cancer cell lines.
 Results: All the synthesized compounds showed the characteristic peaks in Fourier-transform infrared,1H C13NMR, and mass spectral analysis. During docking, all the synthesized compounds 5 (a-r) exhibited higher fitness scores with minimum three bonding interaction with the active site human DHFR (PDB ID: 1KMS). In the MTT assay based on MCF-7 breast cancer cell lines, most of the compounds exhibited significant activity. In the antiproliferative assay against MCF-7 cell lines, most of the compounds exhibited potent activity with IC50 values in micromolar concentrations. Compounds 5a, 5b, 5f, 5h, and 5k have exhibited significant anticancer activity.
 Conclusions: The derivatives were synthesized in quantitative yields. New derivatives possess the antiproliferative activity and antitubercular activity.

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“…The proton nuclear magnetic resonance spectra ( 1 H-NMR) were recorded in CDCl3 on Varian 500 MHz using CDCl 3 . 13 C NMR spectra were measured in CDCl 3 on a Bruker Avance DPX 500 spectrometer at 120 MHz. Chemical shifts (δ) were expressed in ppm and J values in Hertz (Hz).…”

“…Unlike the concurrent administration of two medications, molecular hybridization offers pharmacokinetic benefits over single ligands. [4][5][6] The molecular hybrids comprising the pyrazole-furan backbone have exhibited diverse pharmacological properties such as antibacterial, [7][8][9] anti-Alzheimer,, [10,11] anticancer, [12][13][14][15] antiinflammatory (Cox-1 and Cox-2), [16] and anti-Parkinson's disease (α-synuclein aggregation inhibitor), [17] (Figure 1). Hence, proves to be a useful scaffold in drug design and discovery.…”

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“…The isoxazole structures considered as potential pharmacological agents constitute the most promising five-membered heterocyclic units [74]. Some isoxazoles and related compounds are known to exhibit antitumor [75], anti-HIV [76], anti-inflammatory [77], antioxidant [78], antiviral [79], antimicrobial activities [80] and insecticidal [81]. Currently, there is no approved drug for the treatment of coronaviral disease, although Chloroquine has in vitro activity against SARS-CoV-2.…”