Comparative chemical and biological hydrolytic stability of homologous esters and isosteres.

Esters are one of the major functional groups present in the structures of prodrugs and bioactive compounds. Their presence is often associated with hydrolytic lability. In this paper, we describe a comparative chemical and biological stability of homologous esters and isosteres in base media as well as in rat plasma and rat liver microsomes. Our results provided evidence for the hydrolytic structure lability relationship and demonstrated that the hydrolytic stability in plasma and liver microsome might depend on carboxylesterase activity. Molecular modelling studies were performed in order to understand the experimental data. Taken together, the data could be useful to design bioactive compounds or prodrugs based on the correct choice of the ester subunit, addressing compounds with higher or lower metabolic lability.

Juglone: A Versatile Natural Platform for Obtaining New Bioactive Compounds.

Juglone is a metabolite produced by several species of plants, in particular Juglans nigra. Additionally, juglone is a 1,4-naphthoquinone that has several biological actions. Antimicrobial, antifungal, sedative, oxidizing, antihypertensive, and especially anti-proliferative actions have been described for juglone. This justifies that 1,4-naphthoquinone is a privileged structure for Medicinal Chemistry, and it is useful for the development of new prototypes with varied actions. In this work, we make a profound review of juglone synthesis methodology, the biological actions of juglone, and mainly the synthesis and pharmacological actions of juglone derivatives. We hope that the potent biological actions described for these derivatives in this review will stimulate the continuous design, synthesis, and pharmacological evaluation of new juglone derivatives.

Synthesis and trypanocidal activity of novel pyridinyl-1,3,4-thiadiazole derivatives.

Herein, we present the design, synthesis and trypanocidal evaluation of sixteen new 1,3,4-thiadiazole derivatives from N-aminobenzyl or N-arylhydrazone series. All derivatives were assayed against the trypomastigote form of Trypanosoma cruzi, showing IC50 values ranging from 3 to 226 µM, and a better trypanocidal profile was demonstrated for the 1,3,4-thiadiazole-N-arylhydrazones (3a-g). In this series, the 2-pyridinyl fragment bound to the imine subunit of the hydrazine moiety presented pharmacophoric behavior for trypanocidal activity. Compounds 2a, 11a and 3e presented remarkable activity and excellent selectivity indexes. Compound 2a was also active against the intracellular amastigote form of T. cruzi. Moreover, its corresponding hydrochloride, compound 11a, showed the most promising profile, producing phenotypic changes similar to those caused by posaconazole, a well-known inhibitor of sterol biosynthesis. Thus, 1,3,4-thiadiazole derivative 11a could be considered a good prototype for the development of new drug candidates for Chagas disease therapy.

New 2-amino-pyridinyl-N-acylhydrazones: Synthesis and identification of their mechanism of anti-inflammatory action.

AIMS: The main aim of this paper was the synthesis and the evaluation of the anti-inflammatory activity of LASSBio-1828 (an amino-pyridinyl-N-acylhydrazone) and its respective hydrochloride, based on a p38α MAPK inhibitor (LASSBio-1824) previously synthesized by our group. MAIN METHODS: The compounds were tested regarding their cell viability effect and on acute models of inflammation such as formalin-induced licking test, cell migration and inflammatory mediators quantification. KEY FINDINGS: Treatment with the compounds inhibited p38α, reduced inflammatory pain, cell migration and inflammatory mediators that participate on the MAPK pathway such as TNF-α and IL-1ß. SIGNIFICANCE: Taken together, these results suggest that the synthesis of the corresponding hydrochloride of LASSBio-1828 enhanced its potency as a p38 inhibitor, and also that this compound could be considered a good anti-inflammatory drug candidate after further studies.

NF-κB-IKKß Pathway as a Target for Drug Development: Realities, Challenges and Perspectives.

BACKGROUND: Nuclear factor κB (NF-κB) comprises a family of proteins that act as transcription factors promoting the expression of many genes. Activation of NF-κB biochemical cascades is associated with the regulation of innate and adaptive immune responses and inflammation, among other physiological responses. However, genetic abnormalities and continuous stimulation of the NF- κB-IKKß pathway are directly related to many types of inflammatory and autoimmune diseases, as well as to the genesis and survival of tumor cells. OBJECTIVES: Inhibition of the NF-κB-IKKß cascade can be considered an attractive therapeutic method for the genesis of new prototypes to combat these chronic multifactorial diseases. RESULTS: This review describes some prototypes and drugs that act to inhibit the NF-κB-IKKß pathway, highlighting the realities, challenges and perspectives for therapeutic use. CONCLUSION: Although only proteasome inhibitors, such as bortezomib and carfilzomib, are a reality as therapeutically useful drugs among the known modulators of possible targets in the NF-κB-IKKß pathway, some other prototypes described as IKKß inhibitors have entered clinical stages as drug candidates for the control of inflammatory diseases. It is important to note that some classical drugs available on the pharmaceutical market, such as acetylsalicylic acid, were also described more recently as NF-κB pathway modulators as IKKß inhibitors.

Discovery of naphthyl-N-acylhydrazone p38α MAPK inhibitors with in vivo anti-inflammatory and anti-TNF-α activity.

Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen-activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti-inflammatory profile of new naphthyl-N-acylhydrazone derivatives using animal models. Although all tested compounds (3a-d) have been characterized as p38α MAPK inhibitors and have showed in vivo anti-inflammatory action, LASSBio-1824 (3b) presented the best performance as p38α MAPK inhibitor, with IC50  = 4.45 µm, and also demonstrated to be the most promising anti-inflammatory prototype, with good in vivo anti-TNF-α profile after oral administration.

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-ß (kappa ß 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 0.3 to 30 mg/kg of N-acylhydrazone derivatives was able to significantly reduce leukocyte migration to the cavity. Pretreatment with LASSBio-1524 and its analogues also decreased NO, TNF-α and ROS biosynthesis an events closely involved with NF-kB pathway. The tetrahydronaphthyl-N-acylhydrazone derivative LASSBio-1764 was the most promising compound from this series, surpassing even LASSBio-1524. Additionally, none of the compounds demonstrated myelotoxicity or cytotoxicity. Cell viability was assayed and these compounds demonstrated to be safe at different concentrations. Western blot analysis demonstrated that LASSBio-1524 and LASSBio-1760 inhibited NF-κB expression in RAW 264.7 cell lineage. Our data indicate that the tested compounds have anti-inflammatory activity, which may be related to inhibition of leukocyte migration, reducing the production of NO, TNF-α and ROS. LASSBio-1524 and LASSBio-1760, in addition to these features, also reduced p65 nuclear expression assessed by western blot in RAW 264.7 murine cells.

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. (E)-N'-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)benzylidene)-2-naphthohydrazide hydrochloride (LASSBio-1829 hydrochloride, 10) is a 7-azaindole NAH able to inhibit IKK2 with an IC50 value of 3.8 µm. LASSBio-1829 hydrochloride was found to be active in several pharmacological inflammation tests in vivo, showing its potential as an anti-inflammatory prototype.