TY - JOUR

T1 - Ultrasound Assisted Synthesis and In Silico Modelling of 1,2,4-Triazole Coupled Acetamide Derivatives of 2-(4-Isobutyl phenyl)propanoic acid as Potential Anticancer Agents

AU - Mahmood, Sadaf

AU - Khan, Samreen Gul

AU - Rasul, Azhar

AU - Christensen, Jorn Bolstad

AU - Abourehab, Mohammed A. S.

PY - 2022/11

Y1 - 2022/11

N2 - The development of an economical method for the synthesis of biologically active compounds was the major goal of this research. In the present study, we have reported the ultrasound-radiation-assisted synthesis of a series of novel N-substituted 1,2,4-triazole-2-thiol derivatives. The target compounds 6a-f were efficiently synthesized in significant yields (75-89%) by coupling 1,2,4-triazole of 2-(4-isobutylphenyl) propanoic acid 1 with different electrophiles using ultrasound radiation under different temperatures. The sonication process accelerated the rate of the reaction as well as yielded all derivatives compared to conventional methods. All derivatives were confirmed by spectroscopic (FTIR, (HNMR)-H-1, (CNMR)-C-13, HRMS) and physiochemical methods. All derivatives were further screened for their anticancer effects against the HepG2 cell line. Compound 6d containing two electron-donating methyl moieties demonstrated the most significant anti-proliferative activity with an IC50 value of 13.004 mu g/mL, while compound 6e showed the lowest potency with an IC50 value of 28.399 mu g/mL. The order of anticancer activity was found to be: 6d > 6b > 6f > 6a > 6c > 6e, respectively. The in silico modelling of all derivatives was performed against five different protein targets and the results were consistent with the biological activities. Ligand 6d showed the best binding affinity with the Protein Kinase B (Akt) pocket with the lowest increment G value of -176.152 kcal/mol. Compound 6d has been identified as a promising candidate for treatment of liver cancer.

AB - The development of an economical method for the synthesis of biologically active compounds was the major goal of this research. In the present study, we have reported the ultrasound-radiation-assisted synthesis of a series of novel N-substituted 1,2,4-triazole-2-thiol derivatives. The target compounds 6a-f were efficiently synthesized in significant yields (75-89%) by coupling 1,2,4-triazole of 2-(4-isobutylphenyl) propanoic acid 1 with different electrophiles using ultrasound radiation under different temperatures. The sonication process accelerated the rate of the reaction as well as yielded all derivatives compared to conventional methods. All derivatives were confirmed by spectroscopic (FTIR, (HNMR)-H-1, (CNMR)-C-13, HRMS) and physiochemical methods. All derivatives were further screened for their anticancer effects against the HepG2 cell line. Compound 6d containing two electron-donating methyl moieties demonstrated the most significant anti-proliferative activity with an IC50 value of 13.004 mu g/mL, while compound 6e showed the lowest potency with an IC50 value of 28.399 mu g/mL. The order of anticancer activity was found to be: 6d > 6b > 6f > 6a > 6c > 6e, respectively. The in silico modelling of all derivatives was performed against five different protein targets and the results were consistent with the biological activities. Ligand 6d showed the best binding affinity with the Protein Kinase B (Akt) pocket with the lowest increment G value of -176.152 kcal/mol. Compound 6d has been identified as a promising candidate for treatment of liver cancer.

KW - 2-(4-isobutylphenyl)propanoic acid

KW - acetamides

KW - triazole

KW - in silico modelling

KW - liver cancer

KW - STAT3

KW - HETEROCYCLES

U2 - 10.3390/molecules27227984

DO - 10.3390/molecules27227984

M3 - Journal article

C2 - 36432091

VL - 27

JO - Molecules (Print Archive Edition)

JF - Molecules (Print Archive Edition)

SN - 1431-5157

IS - 22

M1 - 7984

ER -