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In the scope of a research program aimed at developing new drugs for the treatment of central nervous system diseases, we describe herein the synthesis and pharmacological evaluation of 1-(4-(3,5-di-tert-butyl-4-hydroxybenzyl) piperazin-1-yl)-2-methoxyethan-1-one (LQFM180). This compound showed antioxidant activity in two models, electroanalytical assays, and DPPH activity. Moreover, in behavioral tests as the open field test LQFM180 (9.4, 18.8, and 37.6 mg/kg, per oral (p.o.)), we detected anxiolytic-like activity. In the sodium pentobarbital-induced sleep test, LQFM180, in all doses, decreased the latency to sleep and increased sleep duration, indicating central depressant activity; moreover, in the chimney test, LQFM180 did not alter motor activity. LQFM180 (18.8 mg/kg, p.o.) increased the time and number of entries on open arms in the elevated plus maze test, suggesting anxiolytic-like activity, which was reversed by NAN-190 and p-chlorophenylalanine, indicating a role of the serotonergic pathway on this effect. In the forced swimming test, LFQM180 (18.8 mg/kg, p.o.) decreased immobility time, suggesting antidepressant-like activity, which was reversed by monoaminergic antagonists, indicating a role for the serotonergic, noradrenergic, and dopaminergic pathways. Competition binding assays showed that LQFM180 was able to bind to the α1B, 5-HT1A, and D2 receptors, however, within the low micromolar range. We conclude that LQFM180 should be considered as a scaffold for drug candidate development. [ABSTRACT FROM AUTHOR]

In this study, we proposed the design, synthesis of a new compound 2-(4-((1-phenyl-1 H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol ( LQFM032), and pharmacological evaluation of its anxiolytic-like effect. This new compound was subjected to pharmacological screening referred to as Irwin test, prior to sodium pentobarbital-induced sleep, open-field and wire tests. The anxiolytic-like effect of this compound was evaluated using elevated plus maze and light-dark box tests. In addition, the mnemonic activity was evaluated through step-down test. In sodium pentobarbital-induced sleep test, LQFM032 decreased latency and increased duration of sleep. In the open-field test, LQFM032 altered behavioral parameter, that suggested anxiolytic-like activity, as increased in crossings and time spent at the center of open field. In the plus maze test and light-dark box test, the LQFM032 showed anxiolytic-like activity, increased entries and time spent on open arms, and increased in number of transitions and time spent on light area, respectively. Those effects was antagonized by flumazenil but not with 1-(2-Methoxyphenyl)-4-(4-phthalimidobutyl)piperazine ( NAN-190). The LQFM032 did not alter mnemonic activity. Moreover, the anxiolytic-like activity of LQFM032 was antagonized by mecamylamine. In summary, LQFM032 showed benzodiazepine and nicotinic pathways mediated anxiolytic-like activity without altering the mnemonic activity. [ABSTRACT FROM AUTHOR]

Objective The activation of the p53 pathway through the inhibition of MDM2 has been proposed as a novel therapeutic strategy against tumours. A series of cis-imidazoline analogues, termed nutlins, were reported to displace the recombinant p53 protein from its complex with MDM2 by binding to MDM2 in the p53 pocket, and exhibited an antitumour activity both in vitro and in vivo. Thus, the purpose of this study was to evaluate the antitumour properties of LQFM030 ( 2), a nutlin analogue created by employing the strategy of molecular simplification. Methods LQFM030 ( 2) cytotoxicity was evaluated in Ehrlich ascites tumour ( EAT) cells, p53 wild type, by the trypan blue exclusion test, and the mechanisms involved in EAT cell death were investigated by light and fluorescence microscopy, flow cytometry, real-time PCR and Western blotting. Key findings Our results demonstrate that LQFM030 has dose-dependent antiproliferative activity and cytotoxic activity on EAT cells, induces the accumulation of p53 protein and promotes cell cycle arrest and apoptosis. p53 gene transcription was unaffected by LQFM030 ( 2); however, MDM2 m RNA increased and MDM2 protein decreased. Conclusions These results suggest that the small-molecule p53 activator LQFM030 ( 2) has the potential for further development as a novel cancer therapeutic agent. [ABSTRACT FROM AUTHOR]

Background: Pharmacological treatments for mental disorders, such as anxiety and depression, present several limitations and adverse effects. Therefore, new pharmacotherapy with anxiolytic and antidepressant potential is necessary, and the study of compounds capable of interacting with more than one pharmacological target may provide new therapeutic options., Objectives: In this study, we proposed the design, synthesis of a new compound, 2-(4-((1- phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethyl acetate (LQFM192), pharmacological evaluation of its anxiolytic-like and antidepressant-like activities, as well as the possible mechanisms of action involved., Methods: Administration of LQFM192 was carried out prior to the exposure of male Swiss mice to behavioral tests, such as the elevated plus-maze and forced swimming test. The involvement of the serotonergic system was studied by pretreatment with WAY-100635 or p-chlorophenylalanine (PCPA) and the involvement of the benzodiazepine site of the GABAA receptor by pretreatment with flumazenil., Results: The treatment with LQFM192 at doses of 54 and 162 μmol/kg demonstrated anxiolyticlike activity that was blocked by WAY-100635, PCPA, and flumazenil pretreatments. The potential antidepressant-like activity was visualized at the same doses and blocked by WAY-100635 and PCPA., Conclusion: In summary, the anxiolytic-like activity of LQFM192 is mediated by the serotonergic system and the benzodiazepine site of the GABAA receptor, and the antidepressant-like activity through the serotonergic system., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)