Pyridine-Based 1,2,4-Triazolo-Tethered Indole Conjugates Potentially Affecting TNKS and PI3K in Colorectal Cancer

Abstract

A library of pyridine-based 1,2,4-triazolo-tethered indole conjugates were designed, synthesized, and evaluated for anti-proliferative activity against a panel of six human cancer cell lines. All the synthesized conjugates (14a–q) were found to be effective against the HT-29 cell line. Particularly conjugates 14a, 14n, and 14q exhibited promising cytotoxicity, with IC50 values of 1 μM, 2.4 μM, and 3.6 μM, respectively, compared to the standard 5-fluoro­uracil (IC50 = 5.31 μM). Cell cycle arrest at the G0/G1 phase was observed with these compounds, the mitochondrial membrane potential was interrupted, and the total ROS production was enhanced. Western blot and immunofluorescence experiments illustrated that these compounds inhibit the expression of markers that are involved in β-catenin and PI3K pathways. Molecular dynamics simulations demonstrated that compound 14a has major hydrophobic interactions and few H-bonding interactions with both PI3K and tankyrase proteins.

5‐Arylidene‐2,4‐thiazolidinediones as Cysteine Protease Inhibitors against Leishmania Donovani

“…Based on the in vitro cysteine proteases inhibition assay, the most potent compounds inhibit cysteine protease activity. Therefore, performing in silico docking studies for these newly synthesized conjugates against cysteine proteases of Leishmania mexicana CPB proteins was considered interesting using Schrödinger software (Schrödinger's, LLC, New York, NY, USA) with PDB ID 6P4E [45] . Docking scores for this series of compounds have been illustrated in Table 3.…”

“…Therefore, performing in silico docking studies for these newly synthesized conjugates against cysteine proteases of Leishmania mexicana CPB proteins was considered interesting using Schrödinger software (Schrödinger's, LLC, New York, NY, USA) with PDB ID 6P4E. [45] Docking scores for this series of compounds have been illustrated in Table 3. Among all the docked compounds, compound 3 g showed better docking scores against targets (cysteine proteases) and is correlated with the cysteine proteases inhibiting assay activity results.…”

Therapeutic Potential of Methotrexate-Loaded Superparamagnetic Iron Oxide Nanoparticles Coated with Poly(lactic-co-glycolic acid) and Polyethylene Glycol against Breast Cancer: Development, Characterization, and Comprehensive In Vitro Investigation

“…The MCF-7 cells were cultured and subjected to treatment with the IC 50 dose of both the standard and formulations. Following this, the cells were incubated for a duration of 24 h. Following incubation, the medium was extracted, and the cells were retrieved using trypsin EDTA . The collected cells were then placed in a 1.5 mL tube and rinsed once with 500 μL of chilled PBS.…”

Design and Synthesis of Michael Acceptor‐Based Peptidyl β‐Nitrostyrenes as 3CLpro Inhibitors of SARS‐CoV‐2

“…QikProp module version 5.4 of Maestro, was used to calculate the molecular descriptor and predict the ADMET profile of synthesized compounds. [20]…”

“…There are various in silico tools available for predicting the pharmacokinetics of a molecule. QikProp module version 5.4 of Maestro, was used to calculate the molecular descriptor and predict the ADMET profile of synthesized compounds [20] …”