Synthesis of 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) and evaluation of their antioxidant and anticancer activities

Abstract

Background Pyrazoles have attracted particular attention due to the diverse biological activities associated with this heterocyclic system, and some have been shown to be cytotoxic to several human cell lines. Several drugs currently on the market have this heterocycle as the key structural motif, and some have been approved for the treatment of different types of cancer. Results 4,4ʹ-(Arylmethylene)bis(1H-pyrazol-5-ols) derivatives 3a–q were synthetized by a three components reaction of 3-methyl-1-phenyl-5-pyrazolone (1) with various benzaldehydes 2 catalyzed by sodium acetate at room temperature. The structures of all synthesized compounds were characterized by physicochemical properties and spectral means (IR and NMR) and were evaluated for their radical scavenging activity by DPPH assay and tested in vitro on colorectal RKO carcinoma cells in order to determine their cytotoxic properties. All 4,4ʹ-(arylmethylene)bis(1H-pyrazol-5-ols) derivatives 3a–q were synthetized in high to excellent yield, and pure products were isolated by simple filtration. All compounds have good radical scavenging activity, and half of them are more active than ascorbic acid used as standard. Conclusion Several derivatives proved to be cytotoxic in the RKO cell line. In particular, compound 3i proved to be a very potent scavenger with an IC50 of 6.2 ± 0.6 µM and exhibited an IC50 of 9.9 ± 1.1 μM against RKO cell. Autophagy proteins were activated as a survival mechanism, whereas the predominant pathway of death was p53-mediated apoptosis.

Evaluation of the Anti-Leishmania mexicana and -Trypanosoma brucei Activity and Mode of Action of 4,4′-(Arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)

“… a Melting points and spectroscopic data agreed with literature values for all previously reported compounds ( 2a – u ) [ 17 , 26 ]; b using 100% EtOH; c using 50% EtOH; d using 60% EtOH. …”

“…The 4,4′-(arylmethylene)bis(1 H -pyrazol-5-ols) 2a – y was synthetized via a pseudo-three-component-reaction catalyzed by sodium acetate at room temperature in aqueous ethanol, as previously reported [ 17 , 26 ]. The reaction of edaravone ( 1 ) with various benzaldehydes 3 resulted in the corresponding 4,4ʹ-bis-(arilmetilen)bis(1-fenil-3-metil-1 H -pirazol-5-ol) derivatives 2 a – y having a good-to-excellent yield, and pure products were obtained via simple filtration ( Scheme 1 ).…”

“…Several of the compounds tested here have been shown to display radical scavenging activity similar to ( 2b , 2j , 2p , 2q , 2s , 2t , and 2u ) or higher ( 2n and 2r ) than ascorbic acid [ 17 ]. Such activity may be cytoprotective under oxidative stress conditions, but may become cytotoxic under normal growth conditions, given that many essential metabolic reactions rely on radical formation as a mechanistic step for product formation.…”

“…All 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1 H -pyrazol-5-ols) 2 , except 2v-y , were previously reported by our research group and were synthesized using the same procedure [ 17 , 26 ]. Briefly, to a solution of benzaldehyde 3a-y (0.4 mmol) and pyrazole 1 (0.8 mmol) in 4 mL of aqueous ethanol, 1 M NaOAc solution (40.2 µL) was added, and the mixture was stirred at room temperature until the reaction was complete.…”

“…It has also been found to prevent brain edema after ischemia and reperfusion injury in both animal models and stroke patients [ 16 ]. Edaravone derivatives such as 4,4′-(arylmethylene)bis(1 H -pyrazol-5-ols) 2 have a broad spectrum of proven biological activities, including anticancer [ 17 ], anti-inflammatory [ 18 ], antiviral [ 19 ], antifungal [ 18 , 20 ], and antibacterial [ 18 , 20 , 21 , 22 ]. However, regardless of the wide range of reported activities for these heterocycles, there are virtually no studies on their leishmanicidal activity, despite of their structural similarity with 3.3′-(arilmetilen)-bis-(2-hydroxynaphthalen-1,4-diones) [ 23 ], biscoumarins [ 24 ], and 3,3′-diindolylmethanes [ 25 ], some of which exhibit powerful leishmanicidal activity.…”