Synthesis, Structural Modification, and Bioactivity Evaluation of Substituted Acridones as Potent Microtubule Affinity-Regulating Kinase 4 Inhibitors

Maria Voura; Saleha Anwar; Ioanna Sigala; Eleftheria Parasidou; Souzanna Fragoulidou; Md Imtaiyaz Hassan; Vasiliki Sarli

doi:10.1021/acsptsci.3c00084

Synthesis, Structural Modification, and Bioactivity Evaluation of Substituted Acridones as Potent Microtubule Affinity-Regulating Kinase 4 Inhibitors

ACS Pharmacol Transl Sci. 2023 Jul 4;6(7):1052-1074. doi: 10.1021/acsptsci.3c00084. eCollection 2023 Jul 14.

Authors

Maria Voura¹, Saleha Anwar², Ioanna Sigala³, Eleftheria Parasidou¹, Souzanna Fragoulidou¹, Md Imtaiyaz Hassan², Vasiliki Sarli¹

Affiliations

¹ Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece.
² Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
³ Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece.

Abstract

Acridones present numerous pharmacological activities, including inhibition of microtubule affinity-regulating kinase 4 (MARK4) kinase activity. To investigate structure-activity relationships and develop potent MARK4 inhibitors, derivatives of 2-methylacridone were synthesized and tested for their activity against MARK4 kinase. Selective substitutions at the nitrogen atom were accomplished by treating 2-methylacridone with alkyl halides in the presence of K₂CO₃. In addition, amidation of acridone acetic acid 11 with piperazine or tryptophan methyl ester followed by derivatization with various amines gave a series of new acridone derivatives. Among the tested compounds, six were identified as possessing high inhibitory activity against MARK4. The molecular modeling studies showed that the derivatives bearing piperazine or tryptophan bind well to the ATP-binding site of MARK4. The antiproliferative activity of six active compounds was evaluated against HeLa and U87MG cancer cells. Tryptophan derivatives 23a, 23b, and 23c showed significant cytotoxicity against both cell lines with EC₅₀ values ranging from 2.13 to 4.22 μM, while derivatives bearing piperazine were found to be not cytotoxic. Additionally, compound 23a decreased the proliferation of human MDA-MB-435 and U251 cancer cells in the low micromolar range; however, it also affects the non-cancerous HGF cells. Due to their high binding affinity against MARK4, the synthesized compounds could be potential agents to target MARK4 against cancer and tauopathies.