Synthesis and evaluation of pyridinium‐hydrazone derivatives as potential antitumoral agents

Abstract

The hydrazones of 4-hydrazinylpyridinium bearing alkylphenyl groups on pyridinium nitrogen were synthesized and evaluated for their cytotoxic activity against MCF-7, PC3, U2OS, and HEK293 cell lines by Wst1 cell proliferation assay. Cytotoxic activity results indicated that d derivatives having butylene chain; 4 and 5 series having naphthalene and anthracene ring systems showed high cytotoxic activity (IC = 3.27-8.54 μm) on cancer cells. 3d (4-(2-(4-hydroxybenzylidene)hydrazinyl)-1-(4-phenylbutyl)pyridinium bromide) was the most cytotoxic compound with IC value of 3.27 μm against MCF-7. The most active derivatives (1d, 2d, 3d, 4, and 5 series) were selected to investigate for the effects on autophagy by analyzing the expression of autophagy marker proteins. The conversion of LC3-I to its lipidated form LC3-II is essential for autophagy and related to autophagosomes. According to our results, all tested compounds except for 3d induced lipidated form LC3-II accumulation. Then, the effects of the compounds on p62 protein level were also analyzed by the immunoblotting as the autophagy inhibition results in accumulation of p62. Further molecular mechanistic studies including morphological analysis and live-death assays indicated that all tested compounds (1d, 2d, 3d, 4, and 5 series) are potent antitumoral molecules and all except for 3d have potential to inhibit autophagic flux.

Hydrazone analogues with promising antibacterial profiles: Synthesis, morphology, in vitro and in silico approaches

“…Based on the literature survey, the synthesis of hydrazide/hydrazone derivatives with various functional groups was considered by medicinal chemists worldwide. These derivatives possessed a variety of biological activities, comprising antimicrobial (Takaji et al 1997;Khattab et al 2016;Popiołek 2017;Haiba et al 2019;Popiołek, Rysz, et al 2020;Popiołek, Patrejko, et al 2020;Rohane et al 2020Rohane et al ), antiviral (S ßenkardes ß et al 2016Wang et al 2018), antiparasite (Coimbra et al 2019;Tahghighi et al 2020) and anticancer (Tantak et al 2017;Nasr et al 2018;Parlar et al 2018;Popiołek, Patrejko, et al 2020) activities, which confirmed their considerable potential for new drug development. On the other hand, some quinoline derivatives containing hydrazide/hydrazone and other moieties were claimed to have suitable antibacterial (Ajani et al 2018), anticancer (Katariya et al 2020;Puskullu et al 2020), antifungal (El Shehry et al 2018Reginatto et al 2021) and antiparasitic (Bhat et al 2012;Coimbra et al 2013;Tahghighi et al 2020) activities.…”

“…2018; Parlar et al . 2018; Popiołek, Patrejko, et al . 2020) activities, which confirmed their considerable potential for new drug development.…”

The Use of Hydrazones for Biomedical Applications

“…16 Hydroxychloroquine (HCQ) is an autophagy inhibitor and a derivative of the antimalaria chloroquine (CQ), but with the addition of a hydrazone. 15 Wolpin et al conducted clinical trials using HCQ in 20 patients with metastatic pancreatic cancer that did not respond to chemotherapy. 17 Patients received 400 or 600 mg of HCQ twice daily.…”

“…In cancer tissue, autophagy, which removes misfolded proteins and damaged organelles, suppresses the initiation of tumor growth in the early stages of cancer or allows longer survival times in later stages. 15 Because most tumors depend on the autophagy pathway to replenish nutrient homeostasis from the degraded proteins, lipids, and carbohydrates, autophagic inhibitors have been recently investigated as a new form of cancer therapy. 16 Hydroxychloroquine (HCQ) is an autophagy inhibitor and a derivative of the antimalaria chloroquine (CQ), but with the addition of a hydrazone.…”

Synthesis, spectroscopic characterizations and cytotoxic activities of some novel 1,2-bis-(tetrasubstituted-benzylidene) hydrazine analogues

“…Hydrazine and their derivatives are a series of highly active organic molecules [8]. They have important biological activities and this functional groups are found as a core structure in many chemotherapeutic agents having antimicrobial, antimalarial, antileishmanial, antiviral and anticancer effects [9].…”