Synthesis of non‐toxic anticancer active forskolin‐indole‐triazole conjugates along with their in silico succinate dehydrogenase inhibition studies
Ponnam Devendar, Niranjana Kumar Arigari, Satya Srinivas Kalvagunta Venkata Naga, Kotesh Kumar Jonnala, Shilpi Singh, Abha Meena, Pallavi Misra, Suaib Luqman
Abstract
Abstract Biologically important three different pharmacophores, forskolin, indole and 1,2,3‐triazoles are coupled to obtain a hybrid molecule. Here, we described the synthesis of novel series of forskolin‐indole‐triazole conjugates 5a‐5l by using the Cu(I) catalyzed 1,3‐dipolar cycloaddition reaction. Furthermore, the biological significance of the synthesized molecules was assessed by in silico and in vitro modes. All the synthesized compounds were evaluated for in vitro anticancer activity against PC‐3, MCF‐7, MDA‐MB‐231, COLO‐205, HeLa, WRL‐68, RAJI, CHANG and RAW‐264.7 cell lines. Compound 5g was found to be the most potent in all the tested cell lines (IC 50 range 9.6–21.66 μg/ml, except COLO‐205), 5a, 5b and 5k were observed to exert its effect only against WRL‐68 (IC 50 range 27.69–48.18 μg/ml), when compared to parent 3 (IC 50 > 100 μg/ml, tested concentrations 10–50 μg/ml) and standard Doxorubicin (IC 50 range 0.42–3.16 μg/ml). The most potent compound 5g (MEF 50 0.57) was found non‐toxic to human erythrocytes as compared to control (MEF 50 0.60) at tested concentration (50 μg/ml). In silico‐based succinate dehydrogenase inhibition showed that the synthesized compounds were having potent binding affinity compared to forskolin. Predictive ADMET and toxicity risk assessment analysis revealed that most of the compounds were complying with the standard limit of Lipinski's rule of five for oral bioavailability.