Low quality of life and life-threatening conditions often demand pharmacological screening of lead compounds. A spectrum of pharmacological activities has been attributed to pyrazole analogs. The ...substitution, replacement, or removal of functional groups on a pyrazole ring appears consistent with diverse molecular interactions, efficacy, and potency of these analogs. This mini-review explores cytotoxic, cytoprotective, antinociceptive, anti-inflammatory, and antidepressant activities of some pyrazole analogs to advance structure-related pharmacological profiles and rational design of new analogs. Numerous interactions of these derivatives at their targets could impact future research considerations and prospects while offering opportunities for optimizing therapeutic activity with fewer adverse effects.
This study employs electrochemical and Density Functional Theory (DFT) calculation approaches to investigate the potential of a novel analogue of trimetozine (TMZ) antioxidant profile. The ...correlation between oxidative stress and psychological disorders indicates that antioxidants may be an effective alternative treatment option. Butylatedhydroxytoluene (BHT) is a synthetic antioxidant widely used in industry. The BHT-TMZ compound derived from molecular hybridization, known as LQFM289, has shown promising results in early trials, and this study aims to elucidate its electrochemical properties to further support its potential as a therapeutic agent. The electrochemical behavior of LQFM289 was investigated using voltammetry and a mechanism for the redox process was proposed based on the compound’s behavior. LQFM289 exhibits two distinct oxidation peaks: the first peak, Ep1a ≈ 0.49, corresponds to the oxidation of the phenolic fraction (BHT), and the second peak, Ep2a ≈ 1.2 V (vs. Ag/AgCl/KClsat), denotes the oxidation of the amino group from morpholine. Electroanalysis was used to identify the redox potentials of the compound, providing insight into its reactivity and stability in different environments. A redox mechanism was proposed based on the resulting peak potentials. The DFT calculation elucidates the electronic structure of LQFM289, resembling the precursors of molecular hybridization (BHT and TMZ), which may also dictate the pharmacophoric performance.
This study describes the synthetic route and molecular computational docking of LQFM 021, as well as examines its biological effects and toxicity. The docking studies revealed strong interaction of ...LQFM 021 to phosphodiesterase-3 (PDE-3). In isolated arteries, the presence of endothelium potentiates the relaxation for LQFM 021 and the inhibition cyclic nucleotides reduced the relaxation. Pre-contraction with KCl (45 m m ), the treatment with tetraethylammonium (TEA) (5 m m ) and inhibition of reticular Ca2+-ATPase showed an inhibitory effect on relaxation. Moreover, the compound reduced the contraction evoked by the Ca2+ influx. Acute toxicity tests revealed that the compound was practically nontoxic. In conclusion, this study showed that a new synthetic derivative of pyrazole is a possible PDE-3 inhibitor and has vasorelaxant activity and low toxicity.
The LQFM05 is a prototype drug designed for treatment of psychiatric disorders, such as schizophrenia, exhibiting anxiolytic- and antidepressant-like (12 or 24 µmol/kg) effects in classical ...behavioral tests. In order to evaluate its pharmacokinetic properties, a liquid chromatography method coupled to a quadrupole time of flight mass spectrometry system (LC-QTOF/MS) was developed and fully validated for LQFM05 analysis in rat plasma and tissue samples (brain, heart, liver, and kidneys). Liquid-liquid extraction, solid phase extraction and protein precipitation were assessed as clean-up procedures for biological samples and analyte enrichment. Plasma and tissue samples underwent protein precipitation as a preliminary step, using acetonitrile. Linearity was fully demonstrated for the dynamic range (10.0 to 900.0 ng/mL), with r
values higher than 0.99 (RSD
≤ 2%, F
< F
, C
< C
). Biodistribution studies in rats revealed high brain tissue concentrations (12.4 µg/g), suggesting elevated drug affinity to the main therapeutic target tissue, showing a blood partition coefficient of 1.9. Kidneys also showed great exposure and tissue affinity, suggesting a potential extrahepatic clearance. Likewise, all examined tissues exhibited satisfactory LQFMF05 distribution. The mass fragmentation spectrum indicated the presence of its main metabolite, LQFM235, yielded by high hepatic hydroxylation route, an equally bioactive derivative. Lastly, the developed LC-QTOF/MS method was shown to be sensitive (LOQ = 10 ng/mL), precise and accurate for LQFM05 determination in tissue homogenates and plasma samples.
This study reports the biological properties of LQFM030 in vivo, a molecular simplification of the compound nutlin-1.
Ehrlich ascites tumor (EAT)-bearing mice were treated intraperitoneally with ...LQFM030 (50, 75 or 150mg/kg) for 10days to determine changes in ascites tumor volume, body weight, cytotoxicity and angiogenesis. Moreover, flow cytometric expression of p53 and p21 proteins and caspase-3/7, −8 and −9 activation were investigated in EAT cells from mice treated. Acute oral systemic toxicity potential of LQFM030 in mice was also investigated using an alternative method.
Treatment of EAT-bearing mice with LQFM030 resulted in a marked decline in tumor cell proliferation and the vascular endothelial growth factor (VEGF) levels along with enhanced survival of the mice. Apoptotic tumor cell death was detected through p53 and p21 modulation and increase of caspase-3/7, −8 and −9 activity. LQFM030 also showed orally well tolerated, being classified in the UN GHS category 5 (LD50>2000–5000mg/Kg).
LQFM030 seems to be a promising antitumor candidate for combinatory therapy with typical cytotoxic compounds, reducing the toxicity burden while allowing a superior anticancer activity. Moreover, these data also open new perspectives for LQFM030 as an antiangiogenic agent for treatment of diseases involving VEGF overexpression.
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Pyrazoles are potent medicinal scaffolds and exhibit a wide spectrum of biological activities, such as analgesic, anti-inflammatory and antipyretic. In this paper we report on ...research we have performed with the aim of continuing the biological evaluation of the regio-isomeric pyrazole compounds, LQFM-020 (fluorine, para position), LQFM-021 (fluorine, meta position), and LQFM-039 (fluorine, ortho position) in models of pain induced by acidified saline, capsaicin, and formalin. We also investigated the mechanisms of action of these compounds via electrophysiological analyses using the two-electrode voltage-clamp technique and heterologous expression in Xenopus laevis oocytes. This enabled us to study different potassium channel subtypes: the ASIC-1α channel, TRPV-1, and μMOR receptors. Our results indicate that LQFM-020, LQFM-021, and LQFM-039 (15, 30 or 60 mg.kg−1) compounds inhibited the nociceptive response induced by acidified saline in a dose-dependent manner. The dose of 30 mg.kg−1 inhibited the nociceptive response induced by capsaicin by 53.3%, 51.4%, and 52.1%, respectively. In addition, we found that naloxone reverses the antinociceptive effect produced by the compounds in both phases of the formalin test. In electrophysiological analyses, we observed that the LQFM-020, LQFM-021, and LQFM-039 compounds did not modulate voltage-gated K + channel subtypes. In contrast, all the compounds tested inhibited the ASIC-1α channel at pH 4.5, with IC50-values of 96.1, 91.6, and 235.2 μM, respectively. All compounds also inhibited the TRPV-1 channel with IC50-values of 139.1, 212.5, and 159.1 μM, respectively. In contrast to the ASIC-1α and TRPV-1 targets, all compounds showed agonist activity on the μMOR receptor with an EC50-value of 117.4, 98.9, and 86.3 μM, respectively. We thus conclude that the ASIC-1α, TRPV-1, and μMOR channels are targets that are directly involved in the antinociceptive effect of LQFM-020, LQFM-021, and LQFM-039. Furthermore, the modifications of the fluorine positions in the phenyl analogs do not change the analgesic effect. However, LQFM-039 showed lower interaction with ASIC-1α channel.
Over the years, pain has contributed to low life quality, poor health, and economic loss. Opioids are very effective analgesic drugs for treating mild, moderate, or severe pain. Therapeutic ...application of opioids has been limited by short and long-term side effects. These side effects and opioid-overuse crisis has intensified interest in the search for new molecular targets and drugs. The present review focuses on salvinorin A and its analogs with the aim of exploring their structural and pharmacological profiles as clues for the development of safer analgesics. Ethnopharmacological reports and growing preclinical data have demonstrated the antinociceptive effect of salvinorin A and some of its analogs. The pharmacology of analogs modified at C-2 dominates the literature when compared to the ones from other positions. The distinctive binding affinity of these analogs seems to correlate with their chemical structure and
antinociceptive effects. The high susceptibility of salvinorin A to chemical modification makes it an important pharmacological tool for cellular probing and developing analogs with promising analgesic effects. Additional research is still needed to draw reliable conclusions on the therapeutic potential of salvinorin A and its analogs.
The search for new antihypertensive drugs has grown in recent years because of high rate of morbidity among hypertensive patients and several side effects that are associated with the first-line ...medications. The current study sought to investigate the antihypertensive effect of a newly synthesized pyrazole derivative known as 5-(1-(3 fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-21). Spontaneously hypertensive rats (SHR) were used to evaluate the effect of LQFM-21 on mean arterial pressure (MAP), heart rate (HR), renal vascular conductance (RVC), arterial vascular conductance (AVC), baroreflex sensitivity (BRS) index, and vascular reactivity. Acute intravenous (iv) administration of LQFM-21 (0.05, 0.1, 0.2, and 0.4 mg kg
-1
) reduced MAP and HR, and increased RVC and AVC. Chronic oral administration of LQFM-21 (15 mg kg
-1
) for 15 days reduced MAP without altering BRS. The blockade of muscarinic receptors and nitric oxide synthase by intravenous infusion of atropine and
L
-NAME, respectively, attenuated cardiovascular effects of LQFM-21. In addition,
ex vivo
experiments showed that LQFM-21 induced an endothelium-dependent relaxation in isolated aortic rings from SHR. This effect was blocked by guanylyl cyclase inhibitor (ODQ) and
L
-NAME. These findings suggest the involvement of muscarinic receptor and NO/cGMP pathway in the antihypertensive and vasodilator effects of LQFM-21.
Privileged scaffolds are of high importance for molecules containing the pyrazole subunit due to their broad spectrum of pharmacological activities. For this reason, a method that is more efficient ...needs to be developed for the preparation of pyrazole derivatives.
The purpose of this study was the optimisation of the conventional synthesis of the pyrazole ring and the oxidation of phenyl-1H-pyrazole-4-carbaldehyde to phenyl-1H-pyrazole-4-carboxylic acid through Microwave- Assisted Organic Synthesis (MAOS).
We performed a comparison between conventional synthesis and conventional synthesis with microwave heating using the synthesis method of pyrazole ring described by Finar and Godfrey and for the oxidation of phenyl-1H-pyrazole-4-carbaldehyde, the method described by Shriner and Kleiderer was used.
MAOS reduces the reaction time to obtain all compounds compared to conventional heating. At a temperature of 60°C, 5 minutes of reaction time, and power of 50 W, the yield of phenyl-1H-pyrazoles (3a-m) compounds was in the range of 91 - 98% using MAOS, which is better than conventional heating (72 - 90%, 75ºC, 2 hours). An improvement in the yield for the oxidation reaction was also achieved with MAOS. The compounds (5a-m) were obtained with yields ranging from 62 - 92% (80ºC, 2 minutes, 150 W), while the yields with conventional heating were in the range of 48 - 85% (80ºC, 1 hour). The 26 compounds were achieved through an easy work-up procedure with no chromatographic separation. The pure products were characterised by the spectral data obtained from IR, MS,
H and
C NMR or HSQC/HMBC techniques.
The advantages of MAOS include short reaction time and increased yield, due to which it is an attractive option for pyrazole compounds synthesis.
We described herein the design, synthesis, and pharmacological evaluation of N-phenylpiperazine heterocyclic derivatives as multi-target compounds potentially useful for the treatment of ...schizophrenia. The isosteric replacement of the heterocyclic ring at the biaryl motif generating pyrazole, 1,2,3-triazole, and 2-methylimidazole1,2-apyridine derivatives resulted in 21 analogues with different substitutions at the para-biaryl and para-phenylpiperazine positions. Among the compounds prepared, 4 (LASSBio-579) and 10 (LASSBio-664) exhibited an adequate binding profile and a potential for schizophrenia positive symptoms treatment without cataleptogenic effects. Structural features of this molecular scaffold are discussed regarding binding affinity and selectivity for D(2)-like, 5-HT(1A), and 5-HT(2A) receptors.
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