Design, synthesis, biological evaluation, and in silico studies of 2‐aminobenzothiazole derivatives as potent PI3Kα inhibitors

Abstract

A new series of 2-aminobenzothiazole derivatives was designed, synthesized and evaluated for their anticancer activity against the MCF7, MDAMB-231, and HepG2 cancer cell lines. All synthesized derivatives (8a-8n) demonstrated moderate to high anticancer activity against the tested cell lines. As the most potent compound in the series, compound 8i displayed excellent inhibitory potency with an IC 50 value of 6.34 μM and compound 8m displayed an IC 50 value of 8.30 µM against the MCF7 cell line compared to the standard drug HS-173 (IC 50 = 10.25 μM). PI3K enzyme activity assays demonstrated that compound 8i is highly selective against PI3Kα, with an IC 50 value of 1.03 nM. Wound healing assays and cell cycle analysis of compounds 8i and 8m revealed that both compounds suppressed the migration of MCF7 cells and induce cell cycle arrest in the S phase. In the cell death assay, compound 8i was revealed to induce apoptosis in a dose-dependent pattern; further Western blot assays revealed that compound 8i obviously decreases the levels of the antiapoptotic proteins Bcl-xL and Mcl-1. Downregulation of the expression of p-Akt confirmed the PI3K inhibitory activity of compound 8i. The molecular docking and molecular dynamics simulation studies performed were found in agreement with the PI3Kα inhibitory activity assessments performed experimentally.

Molecular docking and dynamics based approach for the identification of kinase inhibitors targeting PI3Kα against non-small cell lung cancer: a computational study

“…The drug-likeness property of the best ten molecules along with the standard PI3K pan-inhibitor Copanlisib was examined and drug-likeness could be analyzed on the basis of Lipinski’s rule of five. 7 Qikprop helps to analyze the drug-likeness property along with other ADMET properties, such as molecular weight, hydrogen bond donation and acceptance, predicted octanol/water partition coefficient (QlogPo/w), polar surface area (PSA), and % human oral absorption. The other descriptors of ADMET analysis and their predictions, such as prediction of aqueous solubility, prediction of IC 50 value for HERG K+ channel blockage, prediction of apparent Caco-2 cell permeability in nm s −1 , etc.…”

“…Among various targets of the disease, phosphoinositide 3-kinases (PI3Ks), also known as phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, and differentiation. 7 There are four types of PI3K: class I, class II, class III, and class IV. They’re divided into groups depending on their primary sequence, management, and lipid substrate selectivity in in vitro studies.…”

Synthesis, biological evaluation, and in silico studies of indole‐tethered pyrazoline derivatives as anticancer agents targeting topoisomerase IIα

“…ELISA reader was used to measure the absorbance at a wavelength of 570 nm. The experiment was repeated three times; the IC 50 values and %cell death were determined by using, excel, Graph pad 5, and AAT Bioquest online calculator (Nawaz et al, 2020; K. Haider, Ahmad, et al, 2022).…”

“…Further transverse sections of each organ were prepared and stained with hematoxylin and eosin. All the prepared slides were observed under an Olympus microscope at ×100 and ×400 magnifications (K. Haider, Ahmad, et al, 2022).…”

“…The simulation study was investigated employing the Simulation Interaction Diagram of Desmond. MD simulation analysis for 100 ns was carried out for the best docking score, showing compound (K. Haider, Ahmad, et al, 2022). The authors are also thankful to the Manipal-Schrodinger Center for Molecular Simulations.…”