Antinociceptive Effects of Aza-Bicyclic Isoxazoline-Acylhydrazone Derivatives in Different Models of Nociception in Mice.

BACKGROUND: In a study recently published by our research group, the isoxazoline-acylhydrazone derivatives R-99 and R-123 presented promising antinociceptive activity. However, the mechanism of action of this compound is still unknown. OBJECTIVE: This study aimed to assess the mechanisms involved in the antinociceptive activity of these compounds in chemical models of pain. METHODS: Animals were orally pretreated and evaluated in the acetic acid-, formalin-, capsaicin-, carrageenan- and Complete Freund's Adjuvant (CFA)-induced pain models in mice. The effects of the compounds after pretreatment with naloxone, prazosin, yohimbine, atropine, L-arginine, or glibenclamide were studied, using the acetic acid-induced writhing test to verify the possible involvement of opioid, α1-adrenergic, α2-adrenergic or cholinergic receptors, and nitric oxide or potassium channels pathways, respectively. RESULTS: R-99 and R-123 compounds showed significant antinociceptive activity on pain models induced by acetic acid, formalin, and capsaicin. Both compounds decreased the mechanical hyperalgesia induced by carrageenan or CFA in mice. The antinociceptive effects of R-99 and R-123 on the acetic acid-induced writhing test were significantly attenuated by pretreatment with naloxone, yohimbine or atropine. R-99 also showed an attenuated response after pretreatment with atropine and glibenclamide. However, on the pretreatment with prazosin, there was no change in the animals' response to both compounds. CONCLUSION: R-99 and R-123 showed antinociceptive effects related to mechanisms that involve, at least in part, interaction with the opioid and adrenergic systems and TRPV1 pathways. The compound R-99 also interacts with the cholinergic pathways and potassium channels.

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents.

Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC50 values of 13.08 µM and 11.38 µM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 µM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 µM).

Structure-guided discovery of thiazolidine-2,4-dione derivatives as a novel class of Leishmania major pteridine reductase 1 inhibitors.

Leishmania major, as other protozoan parasites, plague human kind since pre-historic times but it remains a worldwide ailment for which the therapeutic arsenal remains scarce. Although L. major is pteridine- and purine-auxotroph, well-established folate biosynthesis inhibitors, such as methotrexate, have poor effect over the parasite survival. The lack of efficiency is related to an alternative biochemical pathway in which pteridine reductase 1 (PTR1) plays a major role. For this reason, this enzyme has been considered a promising target for anti-leishmanial drug development and several inhibitors that share the substrate scaffold have been reported. In order to design a novel class of PTR1 inhibitors, we employed the thiazolidinone ring as a bioisosteric replacement for pteridine/purine ring. Among seven novel thiazolidine-2,4-dione derivatives reported herein, 2d was identified as the most promising lead by thermal shift assays (ΔTm = 11 °C, p = 0,01). Kinetic assays reveal that 2d has IC50 = 44.67 ± 1.74 µM and shows a noncompetitive behavior. This information guided docking studies and molecular dynamics simulations (50 000 ps) that supports 2d putative binding profile (H-bonding to Ser-111 and Leu-66) and shall be useful to design more potent inhibitors.

Thiosemicarbazones as Aedes aegypti larvicidal.

A set of aryl- and phenoxymethyl-(thio)semicarbazones were synthetized, characterized and biologically evaluated against the larvae of Aedes aegypti (A. aegypti), the vector responsible for diseases like Dengue and Yellow Fever. (Q)SAR studies were useful for predicting the activities of the compounds not included to create the QSAR model as well as to predict the features of a new compound with improved activity. Docking studies corroborated experimental evidence of AeSCP-2 as a potential target able to explain the larvicidal properties of its compounds. The trend observed between the in silico Docking scores and the in vitro pLC50 (equals -log LC50, at molar concentration) data indicated that the highest larvicidal compounds, or the compounds with the highest values for pLC50, are usually those with the higher docking scores (i.e., greater in silico affinity for the AeSCP-2 target). Determination of cytotoxicity for these compounds in mammal cells demonstrated that the top larvicide compounds are non-toxic.

Synthesis and antimicrobial activities of 5-Arylidene-thiazolidine-2,4-dione derivatives.

Antibiotic resistance is considered one of the world's major public health concerns. The main cause of bacterial resistance is the improper and repeated use of antibiotics. To alleviate this problem, new chemical substances against microorganisms are being synthesized and tested. Thiazolidines are compounds having many pharmacological activities including antimicrobial activities. For this purpose some thiazolidine derivatives substituted at position 5 in the thiazolidine nucleus were synthesized and tested against several microorganisms. Using a disc diffusion method, antimicrobial activity was verified against Gram-positive, Gram-negative, and alcohol acid resistant bacteria and yeast. The minimum inhibition concentrations (MIC) and minimum bactericidal concentrations (MBC) were determined. All derivatives showed antimicrobial activity mainly against Gram-positive bacteria, with MIC values ranging from 2 to 16 µg/mL.

Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents.

In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC(50) of 200-400nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure-activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones.

Synthesis and antitumour evaluation of peptidyl-like derivatives containing the 1,3-benzodioxole system.

In the scope of a research program aiming at the synthesis and pharmacological evaluation of novel possible antitumour prototype compounds, we described in this paper the synthesis of peptidyl-like derivatives containing the 1,3-benzodioxole system. The proliferation inhibitors tested against tumour cell lines identified the derivatives tyrosine (4f) and lysine (4 g) as the most active among them, presenting IC(50) values in micromolar range and are more active than Safrole. For the study on the embryonic development, Safrole did not show any selectivity in this latter assay, which indicates that Safrole acts as a 'cell cycle-nonspecific' inhibitory agent. However, compound 4f presented a fair antimitotic effect, mainly on third cleavage and blastulae stages (38% and 1.7% of normal development, at 10 microg/mL), suggesting a time-dependent activity and a 'cell cycle-specific' agent action. Neither derivatives revealed hemolytic action in assay with mouse erythrocytes.

Genotoxic activity of 3-[3-phenyl-1,2,4-oxadiazol-5-yl] propionic acid and its peptidyl derivatives determined by Ames and SOS response tests.

Compounds derived from 1,2,4-oxadiazole have being reported for their anti-inflammatory activity. However, those compounds should be devoid of any genotoxic side effect. In this work, the genotoxic activity of peptidomimetic moiety-containing 1,2,4-oxadiazoles derivatives was tested based on the Ames and SOS Chromotest. The results showed no mutagenic activity on the Ames test for 3-[3-phenyl-1,2,4-oxadiazol-5-yl] propionic acid (POPA) parental drug, but a weak SOS response induction on Chromotest. The chemical modifications reduced that response to a non-significative level, with l-phenylalanine peptidomimetic derivative being showing the lowest induction response. The results pointed out for the effectiveness of promoting chemical modifications of biological active compounds to increase its mode of action, showed in previous work, without increasing and even decreasing its DNA damage effect.

Synthesis, antitumour and antimicrobial activities of new peptidyl derivatives containing the 1,3-benzodioxole system.

Two series of 5 and 6-substituted 1,3-benzodioxole peptidyl derivatives were synthesized and evaluated as antitumour and antimicrobial agents. The compounds that could be conveniently prepared in a few steps processes from natural safrole have been characterised by IR and 1H-NMR spectroscopy. In vivo antitumor activity tests showed that some of the compounds were able to inhibit carcinoma S-180 tumour growth in mice. The in vitro antimicrobial activity of all compounds revealed that they are able to promote the growth of some organisms, including Bacillus subtilis.