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The thiazolidinone ring is found in compounds that have widespan biology activity and there is mechanism-based evidence that compounds bearing this moiety inhibit P. aeruginosa PhzS (PaPzhS), a key enzyme in the biosynthesis of the virulence factor named pyocyanin. Ten novel thiazolidinone derivatives were synthesised and screened against PaPhzS, using two orthogonal assays. The biological results provided by these and 28 other compounds, whose synthesis had been described, suggest that the dihydroquinazoline ring, found in the previous hit (A- Kd = 18 µM and LE = 0.20), is not required for PaPzhS inhibition, but unsubstituted nitrogen at the thiazolidinone ring is. The molecular simplification approach, pursued in this work, afforded an optimised lead compound (13- 5-(2,4-dimethoxyphenyl)thiazolidine-2,4-dione) with 10-fold improvement in affinity (Kd= 1.68 µM) and more than 100% increase in LE (0.45), which follows the same inhibition mode as the original hit compound (competitive to NADH).Executive summaryPhzS is a key enzyme in the pyocyanin biosynthesis pathway in P. aeruginosa.Orthogonal assays (TSA and FITC) show that fragment-like thiazolidinedione derivatives bind to PaPhzS with one-digit micromolar affinity.Fragment-like thiazolidinedione derivatives bind to the cofactor (NADH) binding site in PaPhzS.The molecular simplification optimised the ligand efficiency and affinity of the lead compound.

Cassia grandis L. (Fabaceae), a native tree from Amazon Forest, has been used in folk medicine against worms and intestinal parasites, and to treat stomach and respiratory problems, blood diseases, among others uses. This study aimed to evaluate the antioxidant, cytotoxic, antimicrobial, and schistosomicidal activities of the methanolic extract from C. grandis stem bark (CgME) and to elucidate the chemical profile of its active fractions. The antioxidant activity of C. grandis stem bark methanolic extract (CgME) and its fractions were determined by DPPH radical scavenging assay and by the total phenolics and flavonoid contents. The antimicrobial activity was performed by microdilution. The cytotoxicity against MCF-7 (breast), NCI-H292 (lung), and HL-60 (leukemia) cancer cell lines was evaluated by the MTT method. The schistosomicidal activity was investigated in vitro against adult Schistosoma mansoni couple worms. The phytochemical profile of the active fractions was determined by GC-MS and UPLC-MS. The hexane fraction from the CgME was cytotoxic to NCI-H292 and HL-60 cancer cell lines and both major compounds clionasterol and lupeol acetate, determined by GC-MS, are well known for their cytotoxicity against cancer cells. The ethyl acetate fraction (CgEF) exhibited both antibacterial, against multidrug-resistant S. aureus, and schistosomicidal activities, which could be attributed to the presence of flavonoids, such as catechin derivatives, quercetin, and luteolin in the CgEF. These results agree with the popular uses of C. grandis and should stimulate future research on this species. Key words: Antimicrobial activity, antioxidant, Staphylococcus aureus, clinical isolates, Schistosoma mansoni, cytotoxicity.

Babassu (Attalea speciosaMart. ex Spreng., Arecaceae) is a palm tree endemic to Brazil and found mainly in the borders of Amazon forest, where the harvesting of its fruits is an important source of income for more than 300,000 people. Among the communities of coconut breakers women, babassu oil is used in culinary, as fuel, and mostly as medicinal oil for the treatment of skin wounds and inflammation. This study aimed to evaluate in vitro and in vivo the wound healing effects of babassu oil. In vitro, babassu oil increased the migration of L929 fibroblasts, inhibited the production of nitric oxide by LPS-stimulated peritoneal macrophages, and increased the levels of INF-γand IL-6 cytokines production. In vivo, babassu oil accelerated the healing process in a full-thickness splinted wound model, by an increase in the fibroblasts number, blood vessels, and collagen deposition in the wounds. The babassu oil also increased the recruitment of inflammatory cells into the wound site and showed an anti-inflammatory effect in a chronic ear edema model, reducing ear thickness, epidermal hyperplasia, and myeloperoxidase activity. Thus, these data corroborate the use of babassu oil in folk medicine as a remedy to treat skin wounds.

Thiazolidine-2,4-dione ring system is used as a pharmacophore to build various heterocyclic compounds aimed to interact with biological targets. In the present study, benzylidene-2,4-thiazolidinedione derivatives (compounds 2 — 5) were synthesized and screened against cancer cell lines and the genotoxicity and cytotoxicity of the most active compound (5) was investigated on normal and lung cancer cell line. For in vitro cytotoxic screening, the MTT assay was used for HL60 and K562 (leukemia), MCF-7 (breast adenocarcinoma), HT29 (colon adenocarcinoma), HEp-2 (cervix carcinoma) and NCI-H292 (lung carcinoma) tumor cell lines and Alamar-blue assay was used for non-tumor cells (PBMC, human peripheral blood mononuclear cells) were used. Cell morphology was visualized after Giemsa-May-Grunwald staining. DNA content, phosphatidylserine externalization and mitochondrial depolarization were measured by flow cytometry. Genotoxicity was assessed by Comet assay. 5-(2-Bromo-5-methoxybenzylidene)-thiazolidine-2,4-dione (5) presented the most potent cytotoxicity, especially against NCI-H292 lung cancer cell line, with IC50 value of 1.26 μg/mL after 72 h incubation. None of the compounds were cytotoxic to PBMC. After 48 h incubation, externalization of phosphatidylserine, mitochondrial depolarization, internucleosomal DNA fragmentation and morphological alterations consistent with apoptosis were observed in NCI-H292 cells treated with compound (5). In addition, compound (5) also induced genotoxicity in NCI-H292 cells (2.8-fold increase in damage index compared to the negative control), but not in PBMC. Compound 5 presented selective cytotoxic and genotoxic activity against pulmonary carcinoma (NCI-H292 cells).

Croton cordiifolius is widely used in Brazilian Caatinga folk medicine to treat general inflammation, pain, and gastrointestinal disturbances. Currently, its medicinal properties are not well understood, owing to the absence of chemical and pharmacological studies. The aims of this work were to analyze the chemical composition of C. cordiifolius stem bark and evaluate its in vitro antioxidant and in vivo anti-inflammatory activities. C. cordiifolius ethanolic extract (CcEE) was obtained by maceration, while essential oil (CcEO) was extracted by hydrodistillation in a Clevenger-type apparatus. The chemical composition was evaluated by thin-layer chromatography and GCMS. Total phenolics, flavonoids, and antioxidant activity were quantitated by spectrophotometry. Topical anti-inflammatory activity was evaluated by different ear edema models in mice. The major compounds in CcEO were α-pinene (51.76%) and β-pinene (19.08%). CcEE analysis indicated the presence of alkaloids, mono- and sesquiterpenes, flavonoids, phenylpropanoids, triterpenes, steroids, and coumarins. CcEE showed antioxidant activity in vitro. In a topical anti-inflammatory assay, CcEO showed no activity. On the contrary, CcEE inhibited ear edema induced by phorbol 12-myristate 13-acetate (PMA), arachidonic acid (AA), ethyl phenylpropriolate (EPP), and phenol. Probable mechanisms include inhibition of AA metabolite biosynthesis, vasoactive amine activity, and cytokine release/activity. These results corroborate the popular reputation of C. cordiifolius as an anti-inflammatory remedy. Key words: Croton cordiifolius, Euphorbiaceae, caatinga, topical anti-inflammatory activity, ear edema.

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 &mu, M and 11.38 &mu, M, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1&delta, /&epsilon, 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 &mu, M). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 &mu, M).

Leishmaniasis is considered as one of the major neglected tropical diseases due to its magnitude and wide geographic distribution. Leishmania braziliensis, responsible for cutaneous leishmaniasis, is the most prevalent species in Brazil. Superoxide dismutase (SOD) belongs to the antioxidant pathway of the parasites and human host. Despite the differences between SOD of Leishmania braziliensis and human make this enzyme a promising target for drug development efforts. No medicinal chemistry effort has been made to identify LbSOD inhibitors. Herein, we show that thermal shift assays (TSA) and fluorescent protein-labeled assays (FPLA) can be employed as primary and secondary screens to achieve this goal. Moreover, we show that thiazole derivatives bind to LbSOD with micromolar affinity.

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.

Lippia sidoides Cham. is widely used in North-East Brazil to treat oral and vaginal infectious diseases due to its strong antimicrobial activity. The aim of this study was to evaluate the antifungal activity of the ethanolic extract of L. sidoides leaves against Candida species isolated from vaginal secretions taken from patients from Pernambuco, Brazil. Antifungal activity was performed by disk diffusion method (2000 μg/disc) and the minimum inhibitory concentration was determined. Fluconazole (25 μg/disc) was used as positive control. A bioautography was carried out to identify the possible active compounds present in the extract. L. sidoides extract was active as fluconazole against most of the 45 Candida strains tested. Eight strains were resistant to fluconazole and sensitive to L. sidoides extract. The bioautography pointed to thymol as the active compound. This study confirmed the ethnomedicinal use of L. sidoides to treat skin and mucosal Candida infections.

Croton cordiifoliusBaill. is a shrub known as “quebra-faca” and is used to treat inflammation, pain, wounds, and gastrointestinal disturbances in the semiarid region in the northeast of Brazil. In an ethnobotanical survey in the state of Pernambuco, “quebra-faca” use was cited in 33% of the interviews. Thus, we decided to evaluate the antinociceptive effects of the essential oil fromC. cordiifolius(CcEO). Chemical analysis by gas chromatography-mass spectrometry revealed 1,8-cineole (25.09%) andα-phellandrene (15.43%) as major constituents. Antinociceptive activity was evaluated using murine models of chemically induced pain (writhing induced by acetic acid, formalin, capsaicin, and glutamate tests). Opioid and central nervous systems (CNS) involvement were also investigated. Regarding antinociceptive activity, CcEO (50 and 100 mg/kg) reduced the number of writhing responses induced by acetic acid and decreased the licking times in both phases of the formalin test. CcEO also was evaluated in capsaicin- and glutamate-induced nociception. While no effect was observed in the capsaicin test, CcEO (100 mg/kg) was effective in the glutamate test. Naloxone, an opioid antagonist, did not affect the antinociceptive activity of CcEO in writhing test. In conclusion, the antinociceptive effect of CcEO could be explained, at least in part, by inhibition of the glutamatergic system.

The acute and chronic treatment of mice with a hydroalcohol extract from the leaves of Cissus sicyoides. L. (Vitaceae) (CS) at doses of 300, 600, and 1000 mg/kg, by intraperitoneal administration, produced a significant central antinociceptive effect on the hot plate, tail immersion, and acetic acid–induced writhing, tests, and the effect was inhibited by naloxone. CS was given to mice daily for 30 days at a dose of 600 mg/kg, causing an effect similar to that of drugs with typical action on opioid receptors. The effective dose (ED50) was approximately 600 mg/kg in mice.

The Hyptis genus has more than 400 species, many of them being used in folk medicine to treat several conditions. Some anticancer compounds have been isolated from plants of this genus, and for that reason we decided to investigate the potential in vivo antitumor activity of extracts of leaves of Hyptis mutabilis with different polarities (hexane, methanol, water, and hot water) against two mice tumors: sarcoma 180 and Ehrlich solid tumor. Phytochemical analysis revealed strong presence of steroids, saponins, flavonoids (mainly dihydroflavanols), and catechins. Acute toxicity was perfomed according to the up-and-down method showing LD50 values ranging from 100 up to 2500 mg/kg. Antitumor activity was investigated using 10% of the LD50 for each extract. Methotrexate was used as positive control. Both aqueous extracts showed strong inhibition of tumor growth with values up to 70% of inhibition growth for sarcoma 180. Ehrlich solid tumor was only slight inhibited by hexane extract (38.6%). In conclusion, the aqueous extracts of H. mutabilis showed promising results against sarcoma 180 mice tumor.

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.

Leaves of Croton adamantinus have been used to treat inflammation and skin wounds in the semi-arid area of the Northeast of Brazil. In order to evaluate if the essential oil (EO) was responsible for the claimed activities; antinociceptive, wound healing and antimicrobial tests were carried out. Twenty constituents were identified in C. adamantinus EO by GC-MS, ¹H-NMR and ¹³C-NMR, the major compounds being methyl-eugenol (14.81%) and 1,8-cineol (13.74%). Antinociceptive activity was evaluated by the formalin test and the abdominal contortion assay in mice. The EO (50 and 100 mg/kg) decreased the licking time of both phases of the formalin test when compared to the vehicle, but not to morphine (7.5 mg/kg). In the abdominal contortion assay, the EO (50 and 100 mg/kg) reduced the number of contortions compared to the vehicle and to indometacin (10 mg/kg). The wound healing activity was verified also using two experimental models: excisional wound and dead space. Topical treatment with the EO (1%) increased the wound contraction from the third day of treatment (compared with nitrofurazone 0.2%), while systemic treatment (50 mg/kg/day) increased granulation tissue formation and reduced the water content. C. adamantinus EO also showed antimicrobial activity against Staphylococcus aureus in disk diffusion method. These results corroborate the ethnobotanical use of this specie by Brazilian population.

Several 5-arylidene-4-thioxo-thiazolidine-2-ones (3a-n) were synthesized and evaluated as antimicrobial agents against representative strains, including multidrug-resistant strains of clinical isolates. Also, the antiproliferative activity was evaluated against two human carcinoma cell lines (NCI-H292 and HEp-2). The compounds containing the 5-arylidene subunit presented greater antimicrobial activities against Gram positive bacteria, including the multidrug-resistant clinical isolates, than the 4-thioxo-thiazolidine-2-one. Important SAR information was also gathered, such as the contribution of thiocarbonyl attached at 4-position on the thiazolidine heterocyclic for antimicrobial properties. None of the derivatives exhibited significant antiproliferative activity against the human carcinoma cell lines.