Adenosine A receptor agonist prevents cardiac remodeling and dysfunction in spontaneously hypertensive male rats after myocardial infarction.

Background: This work evaluated the hypothesis that 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294), an agonist of adenosine A receptor, could be beneficial for preventing cardiac dysfunction due to hypertension associated with myocardial infarction (MI).

Methods: Male spontaneously hypertensive rats (SHR) were randomly divided into four groups (six animals per group): sham-operation (SHR-Sham), and myocardial infarction rats (SHR-MI) were treated orally either with vehicle or LASSBio-294 (10 and 20 mg.kg.

LASSBio-1422: a new molecular scaffold with efficacy in animal models of schizophrenia and disorders of attention and cognition.

Aiming to identify new antipsychotic lead-compounds, our group has been working on the design and synthesis of new N-phenylpiperazine derivatives. Here, we characterized LASSBio-1422 as a pharmacological prototype of this chemical series. Adult male Wistar rats and CF1 mice were used for in-vitro and in-vivo assays, respectively.

Discovery of Novel Orally Active Tetrahydro-Naphthyl-N-Acylhydrazones with In Vivo Anti-TNF-α Effect and Remarkable Anti-Inflammatory Properties.

LASSBio-1524 was designed as inhibitor of the IKK-β (kappa β kinase inhibitor) enzyme, which participates in the activation of the nuclear factor κB (NF-κB) canonical pathway, and its three N-acylhydrazone new analogues, LASSBio-1760, LASSBio-1763 and LASSBio-1764 are now being tested on their anti-inflammatory potential. The activity of these compounds was evaluated with the subcutaneous air pouch induced by carrageenan and by subsequent measurement of tumor necrosis factor-α (TNF-α), nitric oxide (NO) and reactive oxygen species (ROS). In the acute inflammation model, the oral pretreatment with doses from 0.

Treatment with Adenosine Receptor Agonist Ameliorates Pain Induced by Acute and Chronic Inflammation.

Rheumatoid arthritis is an inflammatory autoimmune condition, and tumor necrosis factor-α (TNF-α) plays an important role in its pathophysiology. In vitro, (E)-N'-(3,4-dimethoxybenzylidene)-N-methylbenzohydrazide (LASSBio-1359) has exhibited anti-TNF-α properties, and in vivo these effects are mediated via activation of adenosine receptor. This work investigates the antinociceptive action of LASSBio-1359 in murine models of acute and chronic inflammatory pain.

Beyond the Selective Inhibition of Histone Deacetylase 6.

Histone deacetylase 6 (HDAC6) catalyses the removal of acetyl groups from the lysine residues of a series of non-histone proteins, e.g., α-tubulin, Hsp90 and cortactin.

Understanding the Structural Basis of ALDH-2 Inhibition by Molecular Docking.

Background: The ALDH-2 enzyme has been identified as an important therapeutic target for the development of new drugs for the treatment of cocaine addiction. Several studies involving the synthesis, the design and pharmacological evaluation of daidzin (isoflavonoid inhibitor of ALDH-2) analogs were conducted.

Methods: In this study, we used two in silico approaches effective to understand the mechanism of inhibition of ALDH-2 enzyme, the molecular docking and constructing a pharmacophore model, and we established a correlation between the inhibitory profiles of daidzin and its analog for ALDH-2 and their interaction profiles to understand the structural basis for their inhibitory activities.

Filtering promiscuous compounds in early drug discovery: is it a good idea?

The use of computational filters for excluding supposedly nonspecific and promiscuous compounds from chemical libraries is a controversial issue, because many drugs used in clinics today would never reach the market if these filters were applied. In part, this conflict could be caused by the paradigm: one-drug-one-target, even though it is widely agreed that drug action is a result of a complex network of biomolecular interactions. Therefore, the so-called pan assay interference compounds (PAINS) or promiscuous compounds could be in fact assay artifacts, false positives or, simply, bright chemical matter (BCM) composed of privileged scaffolds, as we propose here.

Evaluation of the antineoplastic activity of gallic acid in oral squamous cell carcinoma under hypoxic conditions.

The purpose of the current study was to develop and test a theoretical model that could explain the mechanism of action of gallic acid (GA) in the oral squamous cell carcinoma context for the first time. The theoretical model was developed using bioinformatics and interaction network analysis to evaluate the effect of GA on oral squamous cell carcinoma. In a second step to confirm theoretical results, migration, invasion, proliferation, and gene expression (Col1A1, E-cadherin, HIF-1α, and caspase-3) were performed under normoxic and hypoxic conditions.

Increasing demonstration of angiogenic markers in skin neoplastic lesions.

Background: Skin cancer represents the most common worldwide malignancy. Angiogenesis is an important factor in tumor growth and metastasis. Given these facts, the purpose of the current study was to compare the levels of angiogenic proteins in the context of the most common malignant and premalignant skin lesions.

Design, Synthesis, and Pharmacological Evaluation of Novel N-Acylhydrazone Derivatives as Potent Histone Deacetylase 6/8 Dual Inhibitors.

This manuscript describes a novel class of N-acylhydrazone (NAH) derivatives that act as histone deacetylase (HDAC) 6/8 dual inhibitors and were designed from the structure of trichostatin A (1). Para-substituted phenyl-hydroxamic acids presented a more potent inhibition of HDAC6/8 than their meta analogs. In addition, the effect of compounds (E)-4-((2-(4-(dimethylamino)benzoyl)hydrazono)methyl)-N-hydroxybenzamide (3c) and (E)-4-((2-(4-(dimethylamino)benzoyl)-2-methylhydrazono)methyl)-N-hydroxybenzamide (3f) on the acetylation of α-tubulin revealed an increased level of acetylation.

LASSBio-579, a prototype antipsychotic drug, and clozapine are effective in novel object recognition task, a recognition memory model.

Previous studies on the N-phenylpiperazine derivative LASSBio-579 have suggested that LASSBio-579 has an atypical antipsychotic profile. It binds to D2, D4 and 5-HT1A receptors and is effective in animal models of schizophrenia symptoms (prepulse inhibition disruption, apomorphine-induced climbing and amphetamine-induced stereotypy). In the current study, we evaluated the effect of LASSBio-579, clozapine (atypical antipsychotic) and haloperidol (typical antipsychotic) in the novel object recognition task, a recognition memory model with translational value.

LASSBio-1829 Hydrochloride: Development of a New Orally Active N-Acylhydrazone IKK2 Inhibitor with Anti-inflammatory Properties.

Inhibitor of nuclear factor κB kinase 2 (IKK2) is suggested to be a potential target for the development of novel anti-inflammatory and anticancer drugs. In this work, we applied structure-based drug design to improve the potency of the inhibitor (E)-N'-(4-nitrobenzylidene)-2-naphthohydrazide (LASSBio-1524, 1 a: IC50 =20 μm). The molecular model built for IKK2 together with the docking methodology employed were able to provide important and consistent information with respect to the structural and chemical inhibitor characteristics that may confer potency to IKK2 inhibitors, providing important guidelines for the development of a new N-acylhydrazone (NAH) derivative.

Fuzzy clustering demonstrates that codon 72 SNP rs1042522 of TP53 gene associated with HNSCC but not with prognoses.

It is estimated that 7.6 million people will die as a consequence of head and neck squamous cell carcinoma (HNSCC). Genetic predisposition has emerged as an important risk factor in the development and prognosis of HNSCC.

Partial agonism and fast dissociation of LASSBio-579 at dopamine D2 receptor.

In an attempt to better understand the molecular mechanism of action of the antipsychotic lead LASSBio-579 and of its main metabolite LQFM 037, the aim of this work was to evaluate their intrinsic activity and binding kinetics at the dopamine D2 receptor. In transfected HEK cells expressing the D2L receptor under an inducible promoter, LASSBio-579 and LQFM 037, but not clozapine, behaved as weak partial agonists in [(35)S]-GTPγS binding assays performed in optimized conditions previously shown to evidence the partial agonist profile of aripiprazole. Besides, data obtained in radioligand competition assays on rat striatal membranes suggested a rapid association to and dissociation from the D2-like receptors.

Bioinformatics, interaction network analysis, and neural networks to characterize gene expression of radicular cyst and periapical granuloma.

Introduction: Bioinformatics has emerged as an important tool to analyze the large amount of data generated by research in different diseases. In this study, gene expression for radicular cysts (RCs) and periapical granulomas (PGs) was characterized based on a leader gene approach.

Methods: A validated bioinformatics algorithm was applied to identify leader genes for RCs and PGs.

Synthesis and Biological Evaluation of Pyrazolo[3,4-b]pyridin-4-ones as a New Class of Topoisomerase II Inhibitors.

A series of 1,3,6-triphenylpyrazolo[3,4-b]pyridin-4-one derivatives was designed, synthesized and evaluated for cytotoxic activity in A375 human melanoma and human erythroleukemia (HEL) cells. The new pyrazolopyridones displayed comparable activities to the antitumor compound etoposide. The inhibitory effect of compounds 17, 18, 27 and 32 against topoisomerase II-mediated cleavage activities was measured finding good correlation with the results obtained from MTS assay.

Antiprotozoal activity of (E)-cinnamic N-acylhydrazone derivatives.

A series of 14 (E)-cinnamic N-acylhydrazone derivatives, designed through molecular hybridization between the (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)prop-2-en-1-one and (E)-3-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)-7-methoxy-2-naphthohydrazide, were tested for in vitro antiparasitic activity upon axenic amastigote forms of Leishmania donovani and bloodstream forms of Trypamosoma brucei rhodesiense. The derivative (2E)-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-N'-[(1E)-phenylmethylene]acrylohydrazide showed moderate antileishmanial activity (IC50 = 6.27 µM) when compared to miltefosine, the reference drug (IC50 = 0.

Acylhydrazone derivatives: a patent review.

Introduction: The N-acylhydrazone (NAH) moiety has been characterized as a privileged structure, capable of providing ligands points for more than one type of bioreceptor. Modifications of the subunits bonded to its acyl and imine functions resulted in several derivatives, which modulate a great diversity of molecular targets. In this context, this patent review reflects the use of the NAH moiety in different compounds.

LASSBio-1135: a dual TRPV1 antagonist and anti-TNF-alpha compound orally effective in models of inflammatory and neuropathic pain.

LASSBio-1135 is an imidazo[1,2-a]pyridine derivative with high efficacy in screening models of nociception and inflammation, presumed as a weak COX-2 inhibitor. In order to tease out its mechanism of action, we investigated others possible target for LASSBio-1135, such as TNF-α and TRPV1, to better characterize it as a multitarget compound useful in the treatment of chronic pain. TRPV1 modulation was assessed in TRPV1-expressing Xenopus oocytes against capsaicin and low pH-induced current.

High expression of S100A4 and endoglin is associated with metastatic disease in head and neck squamous cell carcinoma.

The presence of cervical metastasis is responsible for high morbidity and mortality rates in individuals with head and neck squamous cell carcinoma (HNSCC). S100A4, a pleiotropic EF-hand calcium-binding protein, is expressed in various normal and cancer cell types. During cancer progression, molecular disturbances in S100A4 can modulate the activity and expression of pre-metastatic and metastatic genes.

Novel potent imidazo[1,2-a]pyridine-N-Glycinyl-hydrazone inhibitors of TNF-α production: in vitro and in vivo studies.

In this work, we describe the design, synthesis and pharmacological evaluation of novel imidazo[1,2-a]pyridine-N-glycinyl-hydrazone derivatives (1a-k) intended for use as inhibitors of tumor necrosis factor alpha (TNF-α) production. The compounds were designed based on the orally active anti-inflammatory prototype LASSBio-1504 (2), which decreases the levels of the pro-inflammatory cytokine TNF-α in vitro and in vivo. The in vitro pharmacological evaluation of the imidazo[1,2-a]pyridine compounds (1) showed that substitution of the N-phenylpyrazole core present in prototype 2 by a bioisosteric imidazo[1,2-a]pyridine scaffold generated anti-TNF-α compounds that were more potent than the previously described N-phenylpyrazole derivative 2 and as potent as SB-203580, a p38 MAPK inhibitor.

N-acylhydrazone derivative ameliorates monocrotaline-induced pulmonary hypertension through the modulation of adenosine AA2R activity.

Background: Pulmonary arterial hypertension (PAH) is a disease that results in right ventricular (RV) dysfunction. While pulmonary vascular disease is the primary pathological focus, RV hypertrophy and RV dysfunction are the major determinants of prognosis in PAH. The aim of this study was to investigate the effects of (E)-N'-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio-1386), an N-acylhydrazone derivative, on the lung vasculature and RV dysfunction induced by experimental PAH.

Leptin receptor polymorphism Gln223Arg (rs1137101) in oral squamous cell carcinoma and potentially malignant oral lesions.

The purpose of this study was to assess the LEPR gene Gln223Arg polymorphism (rs1137101) in oral squamous cell carcinoma (OSCC) and in potentially malignant oral lesions (PMOL) in comparison to normal oral mucosa in a Brazilian population. Smokers (n = 89) were selected from a representative sample of 471 individuals from the general population of Montes Claros, Brazil. Participants were age and gender matched to patients with OSCC (n = 25) and oral epithelial dysplasia (n = 25).