Citation: Pele, R.; Marc, G.; Ionut , , I.; Nastas˘ a, C.; Fizes , an, I.; Pîrn ˘ au, A.; Vlase, L.; Palage, M.; Oniga, S.; Oniga, O. Antioxidant and Cytotoxic Activity of New Polyphenolic Derivatives of Quinazolin-4(3H)-one: Synthesis and In Vitro Activities Evaluation. Pharmaceutics 2023, 15, 136. https://doi.org/10.3390/ pharmaceutics15010136 Academic Editors: Tânia S. Morais and Ana M. de Matos Received: 7 December 2022 Revised: 22 December 2022 Accepted: 26 December 2022 Published: 30 December 2022 Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). pharmaceutics Article Antioxidant and Cytotoxic Activity of New Polyphenolic Derivatives of Quinazolin-4(3H)-one: Synthesis and In Vitro Activities Evaluation Raluca Pele 1 , Gabriel Marc 1, * , Ioana Ionut , 1 , Cristina Nastasă 1 , Ionel Fizes , an 2 , Adrian Pîrnău 3 , Laurian Vlase 4 , Mariana Palage 5 , Smaranda Oniga 5 and Ovidiu Oniga 1 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, “Iuliu Hat , ieganu” University of Medicine and Pharmacy, 41 Victor Babes , Street, 400012 Cluj-Napoca, Romania 2 Departmentof Toxicology, Faculty of Pharmacy, “Iuliu Hat , ieganu” University of Medicine and Pharmacy, 8 Victor Babes , , 400012 Cluj-Napoca, Romania 3 National Institute for Research and Development of Isotopic and Molecular Technologies, 400293 Cluj-Napoca, Romania 4 Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu Hat , ieganu” University of Medicine and Pharmacy, 41 Victor Babes , Street, 400012 Cluj-Napoca, Romania 5 Department of Therapeutical Chemistry, Faculty of Pharmacy, “Iuliu Hat , ieganu” University of Medicine and Pharmacy, 12 Ion Creangă, 400010 Cluj-Napoca, Romania * Correspondence: marc.gabriel@umfcluj.ro; Tel.: +40-264-597-256 Abstract: The development of hybrid molecules with significant human therapeutic properties is one of the main approaches of pharmaceutical research. One of the most important pharmacophores is the quinazolin-4(3H)-one heterocycle moiety, due to its wide range of biological activities. By its derivatization with polyphenolic compounds, in our previous research, it proved to possess a good antiradical activity of ortho-diphenolic derivatives of quinazolin-4(3H)-one. In this study, we developed two new series of compounds, with an additional phenolic group or with a methyl group on the thioacetohydrazone fragment. The methods used to evaluate the activity of the compounds were radical scavenging, reduction of oxidizing reagents and transition metals’ ions chelation assays. Quantum descriptors were also calculated in order to evaluate the influence of substituents and their position on the activity of the compounds. The cytotoxic activity was evaluated using normal human foreskin fibroblast cells (BJ) and two cancerous cell lines, lung adenocarcinoma cells (A549) and prostate carcinoma cells (LNCaP). The results obtained for the pyrogallol derivatives showed a high antioxidant activity compared to ascorbic acid and Trolox. All the synthesized compounds displayed a higher cytotoxicity against the cancerous cell types and a high cytocompatibility with the normal cells. The antioxidant activity was deeply influenced by the addition of the third phenolic group in the synthesized molecules. Keywords: quinazolin-4(3H)-one; phenolic derivatives; hybrid molecules; in vitro evaluation; antiox- idant; cytotoxic 1. Introduction The chemical and biological versatility of the quinazolin-4(3H)-one heterocycle moiety is the scientific foundation of our previous research. The following therapeutic charac- teristics, possessed by these derivatives, are known in the scientific literature: anti-HIV, anticancer, antifungal, antibacterial, antimutagenic, anti-inflammatory, anticonvulsant, CNS depressant, antimalarial, antioxidant, anticoccidial and antileishmanial activity [1–10]. Today, the medical and pharmaceutical fields are subject to huge progress, with the help of increasingly advanced technology. An interesting observation emphasizes oxidative stress and its effects on the human body. Continuous oxidative stress can be harmful to human cells and can ultimately lead to chronic inflammation. By activating transcription Pharmaceutics 2023, 15, 136. https://doi.org/10.3390/pharmaceutics15010136 https://www.mdpi.com/journal/pharmaceutics