Ultrasound-Promoted Synthesis of 3-(Thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamides and Anticancer Activity Evaluation in Leukemia Cell Lines

Abstract

3-(Thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamides were efficiently prepared through a cyclocondensation of thiophenylchalcones with aminoguanidine hydrochloride under ultrasonic conditions in the presence of KOH and ethanol as a green solvent in short reaction times (15-35 min) and good yields (62-95%). All compounds produced were evaluated against the human Jurkat and RS4;11 acute lymphoblastic leukemia cell lines of T-and B-cell origin, respectively, and the K562 myelogenous leukemia cell line. Six compounds presented half maximal inhibitory concentration (IC 50 ) values around 15 µmol L -1 and five compounds presented IC 50 values around 40 µmol L -1 for at least one of the three cell lines analyzed. One compound was not significantly cytotoxic, presenting IC 50 value > 100 µmol L -1 . Keywords: amidinopyrazole, pyrazoline, cytotoxic activity, leukemia, ultrasonic irradiation IntroductionAmidine functional group has proven to be an important fragment in compounds with recognized bioactivities. In this sense, several amidines have been prepared and their antifungal, 1 antiprotozoal, 2 antibacterial, 3 anti-HIV, 4 antithrombotic, 5 and antidegenerative 6 potentials have been evaluated. Pentamidine is clinically used for treatment of pneumonia and first stage human African tripanosomiasis. 7 That drug is on the WHO's List of Essential Medicines for the basic health system. 8 Moreover, amidine containing molecules have been pointed as proeminent prototypes in the search for new anticancer agents. 9 In addition, thiophene-2-carboximidamides have shown potent and selective inhibitory activities of nitric oxide synthases for the treatment of human melanoma. 10In the same context, pyrazoles are recognized as a fundamental class of heterocyclic compounds because of their well-established applicability in several areas as agrochemicals, functional materials and medicines. Ultrasound-Promoted Synthesis of 3-(Thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamides J. Braz. Chem. Soc. 218 Taking into account the valuable pharmacological properties of pyrazoline and amidine scaffolds, we envisioned that hybrid molecules could be active against leukemia cells. Analogous 4,5-dihydro-1H-pyrazole-1-carboximidamides have been already prepared by the cyclocondensation of α,β-unsaturated ketones with aminoguanidine free base under conventional 17 and sonochemical 18 conditions. However, to the best of our knowledge there are not reported studies about the antileukemic potency of these hybrid molecules.Thus, in our continuous efforts to develop sonochemically promoted reactions in environmentally benign solvents 19 and synthetic methodologies for preparation of heterocyclic compounds 20 selected on the basis of their biological activity, 21 we describe herein a rapid and efficient synthetic method for the preparation of 3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamide hydrochlorides under ultrasonic conditions. In addition, all compounds synthetized were evaluated against the human Jurkat and RS4;11 a...

(R,S)-5-(4-Chlorophenyl)-3-{(E)-2-[(R,S)-2,6,6-trimethylcyclohex-2-en-1-yl]vinyl}-4,5-dihydro-1H-pyrazole-1-carboximidamide Hydrochloride

“…Recently, we have reported that ultrasonic irradiation was valuable in promoting the cyclocondensation reaction of chalcones and aminoguanidine hydrochloride for the synthesis of amidino pyrazolines [9][10][11]. This method prompted us to synthesize series of pyrazolines in short reaction times and good yields using ethanol as green solvent, despite the low solubility of aminoguanidine in such medium.…”