Selenazolyl-hydrazones as Novel Selective MAO Inhibitors With Antiproliferative and Antioxidant Activities: Experimental and In-silico Studies

Abstract

The novel approach in the treatment of complex multifactorial diseases, such as neurodegenerative disorders and cancer, requires a development of efficient multi-targeting oriented drugs. Since oxidative stress significantly contributes to the pathogenesis of cancer and neurodegenerative disorders, potential drug candidates should possess good antioxidant properties. Due to promising biological activities shown for structurally related (1,3-thiazol-2-yl)hydrazones, a focused library of 12 structurally related benzylidene-based (1,3-selenazol-2-yl)hydrazones was designed as potential multi-targeting compounds. Monoamine oxidases (MAO) A/B inhibition properties of this class of compounds have been investigated. Surprisingly, the p-nitrophenyl-substituted (1,3-selenazol-2-yl)hydrazone 4 showed MAO B inhibition in a nanomolar concentration range (IC50 = 73 nM). Excellent antioxidant properties were confirmed in a number of different in vitro assays. Antiproliferative activity screening on a panel of six human solid tumor cell lines showed that potencies of some of the investigated compounds was comparable or even better than that of the positive control 5-fluorouracil. In-silico calculations of ADME properties pointed to promising good pharmacokinetic profiles of investigated compounds. Docking studies suggest that some compounds, compared to positive controls, have the ability to strongly interact with targets relevant to cancer such as 5′-nucleotidase, and to neurodegenerative diseases such as the small conductance calcium-activated potassium channel protein 1, in addition to confirmation of inhibitory binding at MAO B.

Masked Phenolic-Selenium Conjugates: Potent and Selective Antiproliferative Agents Overcoming P-gp Resistance

“…Besides tumour cells, the most active compounds were also tested against the non-tumour cell line BJ-hTert (fibroblasts). In both cases, the NCI protocol, with minor modifications [54], was followed; selected data, including the selectivity index (S.I.) can be found in Table 3 and full data in Supporting Information (Table S1).…”

“…The in vitro antiproliferative activity was assayed using minor modifications of the protocol of the National Cancer Institute (NCI) of the United States against the six human solid tumor cell and the non-tumor cell lines tested [54].…”

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

“…Elshaflu et al designed a series of benzylidene‐based (1,3‐selenazol‐2‐yl)hydrazones and evaluated them for MAO‐B inhibition property (Figure ). The 2‐(2‐(4‐nitrobenzylidene)hydrazinyl)‐4‐phenyl‐1,3‐selenazole 221 showed MAO‐B inhibition in a nanomolar concentration range (IC 50 = 73 nM) compared to similar substitution at ortho and meta positions.…”

“…Selenazolyl‐hydrazones ( 221 ) and sulfonyl hydrazones ( 222 ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration…”

2H/4H-Chromenes—A Versatile Biologically Attractive Scaffold

“…One of the essential structural features of 4H-ch to impart miscellaneous activity is the occurrence of the fold along the oxygen axis. The molecules containing 2H/4H-ch scaffold exhibit noteworthy potency, such as anticancer (Afifi et al, 2017a ; Halawa et al, 2017 ; Elshaflu et al, 2018 ; Elnaggar et al, 2019 ; Luque-Agudo et al, 2019 ), anticonvulsant (Rawat and Verma, 2016 ), antimicrobial (Suvarna et al, 2017 ; Mashhadinezhad et al, 2019 ), anticholinesterase (Tehrani et al, 2019 ), antidiabetic activities (Soni et al, 2019 ), antituberculosis (Zhao et al, 2020 ), and inhibitory activity against monoamine oxidase (MAO) (Takao et al, 2019 ).…”