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Finding new chemicals or adjuvants with analgesic effects in the central nervous system is clinically relevant due to the limited number of drugs with these properties. Here, we present PT-31, which is chemically related to 3-benzyl-imidazolidine, with an analgesic profile that results from alpha(2)-adrenoceptor activation. Intraperitoneal administration of PT-31 dose-dependently produced antinociception in the hot plate test, and interacted synergistically with morphine. This effect was completely reversed by yohimbine, a non-selective antagonist of alpha(2)-adrenoceptors, and by BRL 44408, a selective alpha(2A)-adrenoceptor antagonist. The combination of morphine and PT-31 produced greater antinociceptive activity than either alone, and isobolographic analysis revealed a synergistic interaction between these compounds. Docking results confirm the high affinity of the PT-31 ligand at the alpha(2A)-adrenoceptor. PERSPECTIVE: This study introduces a new analgesic compound (PT-31) that acts via alpha(2A)-adrenoceptor activation. A significant increase in analgesia was observed when co-administered with morphine. PT-31 is an interesting new substance for pain therapy. [ABSTRACT FROM AUTHOR]

Trypanosoma cruzi (T. cruzi) causes Chagas, which is a neglected tropical disease (NTD). WHO estimates that 6 to 7 million people are infected worldwide. Current treatment is done with benznidazole (BZN), which is very toxic and effective only in the acute phase of the disease. In this work, we designed, synthesized, and characterized thirteen new phenoxyhydrazine-thiazole compounds and applied molecular docking and in vitro methods to investigate cell cytotoxicity, trypanocide activity, nitric oxide (NO) production, cell death, and immunomodulation. We observed a higher predicted affinity of the compounds for the squalene synthase and 14-alpha demethylase enzymes of T. cruzi. Moreover, the compounds displayed a higher predicted affinity for human TLR2 and TLR4, were mildly toxic in vitro for most mammalian cell types tested, and LIZ531 (IC50 2.8 μM) was highly toxic for epimastigotes, LIZ311 (IC50 8.6 μM) for trypomastigotes, and LIZ331 (IC50 1.9 μM) for amastigotes. We observed that LIZ311 (IC50 2.5 μM), LIZ431 (IC50 4.1 μM) and LIZ531 (IC50 5 μM) induced 200 μg/mL of NO and JM14 induced NO production in three different concentrations tested. The compound LIZ331 induced the production of TNF and IL-6. LIZ311 induced the secretion of TNF, IFNγ, IL-2, IL-4, IL-10, and IL-17, cell death by apoptosis, decreased acidic compartment formation, and induced changes in the mitochondrial membrane potential. Taken together, LIZ311 is a promising anti-T. cruzi compound is not toxic to mammalian cells and has increased antiparasitic activity and immunomodulatory properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice., Experimental Approach: Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured., Key Results: Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF., Conclusion and Implications: TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients., (© 2023 British Pharmacological Society.)

Objective: In this study, we have synthesized 19 Thiazolidine (TZD) derivatives to investigate their potential anti-ZIKV effects., Methods: Nineteen thiazolidine derivatives were synthesized and evaluated for their cytotoxicity and antiviral activity against the ZIKA virus., Results: Among them, six demonstrated remarkable selectivity against the ZIKV virus, exhibiting IC50 values of <5μM, and the other compounds did not demonstrate selectivity for the virus. Interestingly, several derivatives effectively suppressed the replication of ZIKV RNA copies, with derivatives significantly reducing ZIKV mRNA levels at 24 hours post-infection (hpi). Notably, two derivatives (ZKC-4 and -9) stood out by demonstrating a protective effect against ZIKV cell entry. Informed by computational analysis of binding affinity and intermolecular interactions within the NS5 domain's N-7 and O'2 positions, ZKC-4 and FT-39 displayed the highest predicted affinities. Intriguingly, ZKC-4 and ZKC-9 derivatives exhibited the most favorable predicted binding affinities for the ZIKV-E binding site., Conclusion: The significance of TZDs as potent antiviral agents is underscored by these findings, suggesting that exploring TZD derivatives holds promise for advancing antiviral therapeutic strategies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Tuberculosis remains a major public health problem and one of the top ten causes of death worldwide. The alarming increase in multidrug-resistant and extensively resistant variants (MDR, pre-XDR, and XDR) makes the disease more difficult to treat and control. New drugs that act against MDR/XDR strains are needed for programs to contain this major epidemic. The present study aimed to evaluate new compounds related to dihydro-sphingosine and ethambutol against sensitive and pre-XDR Mycobacterium strains, as well as to characterize the pharmacological activity through in vitro and in silico approaches in mmpL3 protein. Of the 48 compounds analyzed, 11 demonstrated good to moderate activity on sensitive and MDR Mycobacterium tuberculosis (Mtb), with a Minimum Inhibitory Concentration (MIC) ranging from 1.5 to 8 μM. They presented 2 to 14 times greater potency of activity when compared to ethambutol in pre-XDR strain, and demonstrated a selectivity index varying between 2.21 and 82.17. The substance 12b when combined with rifampicin, showed a synergistic effect (FICI = 0.5) on sensitive and MDR Mtb. It has also been shown to have a concentration-dependent intracellular bactericidal effect, and a time-dependent bactericidal effect in M. smegmatis and pre-XDR M. tuberculosis. The binding mode of the compounds in its cavity was identified through molecular docking and using a predicted structural model of mmpL3. Finally, we observed by transmission electron microscopy the induction of damage to the cell wall integrity of M. tuberculosis treated with the substance 12b. With these findings, we demonstrate the potential of a 2-aminoalkanol derivative to be a prototype substance and candidate for further optimization of molecular structure and anti-tubercular activity in preclinical studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Chagas disease is an important neglected disease that affects 6-7 million people worldwide. The disease has two phases: acute and chronic, in which there are different clinical symptoms. Controlling the infection depends on innate and acquired immune responses, which are activated during the initial infection and are critical for host survival. Furthermore, the immune system plays an important role in the therapeutic success. Here we summarize the importance of the immune system cytokines in the pathology outcome, as well as in the treatment., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

NPCdc is a natriuretic peptide synthesized from the amino acid sequence of the Crotalus durissus cascavella snake venom peptide, NP2Casca. NPCdc presents hypotensive and antioxidants effects. This study aimed to investigate in vivo whether angiotensin I-converting enzyme (ACE) inhibition would influence the impact of NPCdc in arterial pressure of rats submitted to 5/6 nephrectomy (Nx). Adult male Wistar rats following a 5/6 Nx were treated with enalapril (NxE group, 10 mg/kg/day, n = 9) or vehicle (Nx group, n = 8) for two weeks. On the 15th day after Nx, rats were anaesthetized and submitted to mean arterial pressure (MAP) determination before and after receiving two intravenous injections of saline (vehicle, n = 9) or NPCdc (0.3 μg/kg dissolved in saline, n = 18) separated by a 20-min interval. The kidneys were submitted to oxidative stress analysis. The basal MAP of the NxE group was nearly 20% lower (P < 0.05) than non-treated rats. NPCdc administration decreased the MAP in both groups; however, in the NxE group, the effects were observed only in the second injection. The peptide also decreased the NADPH oxidase activity in the renal cortex. Additionally, the hydrolysis of NPCdc by recombinant neprilysin (NEP) was monitored by mass spectrometry. NPCdc was cleaved by NEP at different peptides with an inhibition constant (Ki) of 1.5 μM, determined by a competitive assay using the NEP fluorescence resonance energy transfer (FRET) peptide substrate Abz-(d)Arg-Gly-Leu-EDDnp. Docking experiments confirmed the high affinity of NPCdc toward NEP. These findings provide new insights into the antihypertensive and antioxidant mechanism of action of NPCdc. Altogether, the results presented here suggest that NPCdc must be further studied as a potential therapy for cardiorenal syndromes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Streptomyces hygroscopicus UFPEDA 3370 was fermented in submerged cultivation and the biomass extract was partitioned, obtaining a fraction purified named EB1. After purification of EB1 fraction, nigericin free acid was obtained and identified. Nigericin presented cytotoxic activity against several cancer cell lines, being most active against HL-60 (human leukemia) and HCT-116 (human colon carcinoma) cell lines, presenting IC 50 and (IS) values: 0.0014 μM, (30.0) and 0.0138 μM (3.0), respectively. On HCT-116, nigericin caused apoptosis and autophagy. In this study, nigericin was also screened both in vitro and in silico against a panel of cancer-related kinases. Nigericin was able to inhibit both JAK3 and GSK-3β kinases in vitro and its binding affinities were mapped through the intermolecular interactions with each target in silico., (Copyright © 2020. Published by Elsevier B.V.)

Background: A safe and effective vaccine against human leishmaniasis still requires the identification of better antigens for immunization and adequate models to evaluate the immune response. To support vaccine development, this work tested the immunogenicity of 10 different peptides derived from the proteome of Leishmania braziliensis , which were selected by their in silico affinity to MHC complexes. Research design and Methods: Comparative cell proliferation assays were performed by culturing, in the presence of each peptide, PBMC cells from subclinical subjects (SC), cutaneous leishmaniasis patients with active disease (AD), post-treatment (PT) individuals, and healthy controls. Culture supernatants were then used for Th1, Th2, and Th17 cytokine measurements. Cells from selected PT samples were also used to assess the expression, by T cells, of the T-bet Th1 transcription factor. Results: A robust cell proliferation was observed for the SC group, for all the tested peptides. The levels of Th1 cytokines were peptide-dependent and had substantial variations between groups, where, for instance, IFN-γ and TNF levels were some of the highest, particularly on PT cultures, when compared to IL-2. On the other hand, Th2 cytokines displayed much less variation. IL-6 was the most abundant among all the evaluated cytokines while IL-4 and IL-10 could be found at much lower concentrations. IL-17 was also detected with variations in SC and AD groups. T-bet was up-regulated in CD4 + and CD8 + T cells from the PT group after stimulation with all peptides. Conclusions: The peptide epitopes can differentially stimulate cells from SC, AD, and PT individuals, leading to distinct immune responses., (Copyright © 2020 e Silva, de Oliveira, da Silva, Brelaz de Castro, Ferreira, Hernandes, de Brito, de-Melo-Neto, Rezende and Pereira.)

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 IC 50 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 3 c 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).

Leishmaniasis is a neglected disease that affects millions of individuals around the world. Regardless of clinical form, treatment is based primarily on the use of pentavalent antimonials. However, such treatments are prolonged and present intense side effects, which lead to patient abandonment in many cases. The search for chemotherapeutic alternatives has become a priority. Heat Shock Protein 90 (Hsp90) inhibitors have recently come under investigation due to antiparasitic activity in Plasmodium sp., Trypanosoma sp. and Leishmania sp. Some of these inhibitors, such as geldanamycin and its analogs, 17-AAG and 17-DMAG, bind directly to Hsp90, thereby inhibiting its activity. Previous studies have demonstrated that different parasite species are more susceptible to some of these inhibitors than host cells. We hypothesized that this increased susceptibility may be due to differences in binding of Hsp90 inhibitors to Leishmania protein compared to host protein. Based on the results of the in silico approach used in the present study, we propose that geldanamycin, 17-AAG and 17-DMAG present an increased tendency to bind to the N-terminal domain of Leishmania amazonensis Hsp83 in comparison to human Hsp90. This could be partially explained by differences in intermolecular interactions between each of these inhibitors and Hsp83 or Hsp90. The present findings demonstrate potential for the use of these inhibitors in the context of anti-Leishmania therapy.

The treatment of chronic pain remains a challenge for clinicians worldwide, independent of its pathogenesis. It motivates several studies attempting to discover strategies to treat the disease. The in silico analysis using molecular docking approach demonstrated that the phthalimide N-(4methyl-phenyl)-4-methylphthalimide (MPMPH-1) presented high affinity to adenylyl-cyclase enzyme (AC). It also prominently reduced the mechanical hypersensitivity of mice challenged by Forskolin, an AC activator. This effect lasted for up to 48h after Forskolin injection, presenting activity longer than MDL-12330A (AC inhibitor). MPMPH-1 was also effective in reducing the hypersensitivity induced by IL-1β, bradykinin, prostaglandin E 2 or epinephrine, chemical mediators that have, among others, AC as pivotal protein in their signalling cascade to induce mechanical-pain behaviour. The compound presented marked inhibition in inflammatory-pain models induced by carrageenan, lipopolysaccharide or complete Freund's adjuvant, including neutrophil migration inhibition. Furthermore, it also seems to act in both peripheral and pain central-control pathways, being also effective in reducing the persistent cancer-pain behaviour induced by melanoma cells in mice. MPMPH-1 could represent a promising pharmacological tool to treat acute and chronic painful diseases, with good bioavailability, local activity, and lack of locomotor-activity interference. Further studies are necessary to determine the exact mechanism of action but it seems to involve AC enzyme as possible target., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Supramolecular interactions between β-lapachone (β-lap) and cyclodextrins (CDs) were investigated by isothermal titration calorimetry. The most favorable host: guest interaction was characterized using X-ray powder diffraction (XRD), differential scanning calorimetry and thermogravimetry (DSC/TG), spectroscopy (FT-IR), spectroscopy (2D ROESY) nuclear magnetic resonance (NMR), and molecular modeling. Phase solubility diagrams showed β-, HP-β-, SBE-β-, γ-, and HP-γ-CDs at 1.5% (w/w) allowed an increase in apparent solubility of β-lap with enhancement factors of 12.0, 10.1, 11.8, 2.4, and 2.2, respectively. β-lap has a weak interaction with γ- and HP-γ-CDs and tends to interact more favorably with β-CD and its derivatives, especially SBE-β-CD (K = 4160 M -1 ; ΔG = -20.66 kJ·mol -1 ). Thermodynamic analysis suggests a hydrophobic interaction associated with the displacement of water from the cavity of the CD by the β-lap. In addition, van der Waals forces and hydrogen bonds were responsible for the formation of complexes. Taken together, the results showed intermolecular interactions between β-lap and SBE-β-CD, thereby confirming the formation of the inclusion complex. Molecular docking results showed 2 main orientations in which the interaction of benzene moiety at the wider rim of the SBE-β-CD is the most stable (average docking energy of -7.0 kcal/mol). In conclusion, β-lap:SBE-β-CD is proposed as an approach for use in drug delivery systems in cancer research., (Copyright © 2017 John Wiley & Sons, Ltd.)

In this pioneer study, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was used to improve the solubility of the diffractaic acid (DA) via inclusion complex (DA:HP-β-CD). Subsequently, DA:HP-β-CD was incorporated into poly-ε-caprolactone (PCL) microspheres (DA:HP-β-CD-MS). Microspheres containing DA (DA-MS) or DA:HP-β-CD (DA:HP-β-CD-MS) were prepared using the multiple W/O/W emulsion-solvent evaporation technique. The phase-solubility diagram of DA in HP-β-CD (10-50mM) showed an A L type curve with a stability constant K 1:1 =821M -1 . 1 H NMR, FTIR, X-ray diffraction and thermal analysis showed changes in the molecular environment of DA in DA:HP-β-CD. The molecular modeling approach suggests a guest-host complex formation between the carboxylic moiety of both DA and the host (HP-β-CD). The mean particle size of the microspheres were ∅ DA-MS =5.23±1.65μm and ∅ DA:HP-β-CD-MS =4.11±1.39μm, respectively. The zeta potential values of the microspheres were ζ DA-MS =-7.85±0.32mV and ζ DA:HP-β-CD-MS =-6.93±0.46mV. Moreover, the encapsulation of DA:HP-β-CD into microspheres resulted in a more slower release (k 2 =0.042±0.001; r 2 =0.996) when compared with DA-MS (k 2 =0.183±0.005; r 2 =0.996). The encapsulation of DA or DA:HP-β-CD into microspheres reduced the cytotoxicity of DA (IC 50 =43.29μM) against Vero cells (IC 50 of DA-MS=108.48μM and IC 50 of DA:HP-β-CD-MS=142.63μM)., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In previous studies, the compound 3-(bromopropiophenone) thiosemicarbazone was described as a potent anti-Trypanosoma cruzi and cruzain inhibitor. In view to optimize this activity, 1,3-thiazole core was used as building-block strategy to access new lead generation of anti T. cruzi agents. In this way a series of thiazole derivatives were synthesized and most of these derivatives exhibited antiparasitic activity similar to benznidazole (Bzd). Among them, compounds (1c) and (1g) presented better selective index (SI) than Bzd. In addition, compounds showed inhibitory activity against the cruzain protease. As observed by electron microscopy, compound (1c) treatment caused irreversible and specific morphological changes on ultrastructure organization of T. cruzi, demonstrating that this class of compounds is killing parasites., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The leishmaniases are neglected tropical diseases widespread throughout the globe, which are caused by protozoans from the genus Leishmania and are transmitted by infected phlebotomine flies. The development of a safe and effective vaccine against these diseases has been seen as the best alternative to control and reduce the number of cases. To support vaccine development, this work has applied an in silico approach to search for high potential peptide epitopes able to bind to different major histocompatibility complex Class I and Class II (MHC I and MHC II) molecules from different human populations. First, the predicted proteome of Leishmania braziliensis was compared and analyzed by modern linear programs to find epitopes with the capacity to trigger an immune response. This approach resulted in thousands of epitopes derived from 8,000 proteins conserved among different Leishmania species. Epitopes from proteins similar to those found in host species were excluded, and epitopes from proteins conserved between different Leishmania species and belonging to surface proteins were preferentially selected. The resulting epitopes were then clustered, to avoid redundancies, resulting in a total of 230 individual epitopes for MHC I and 2,319 for MHC II. These were used for molecular modeling and docking with MHC structures retrieved from the Protein Data Bank. Molecular docking then ranked epitopes based on their predicted binding affinity to both MHC I and II. Peptides corresponding to the top 10 ranked epitopes were synthesized and evaluated in vitro for their capacity to stimulate peripheral blood mononuclear cells (PBMC) from post-treated cutaneous leishmaniasis patients, with PBMC from healthy donors used as control. From the 10 peptides tested, 50% showed to be immunogenic and capable to stimulate the proliferation of lymphocytes from recovered individuals.

Peroxisome proliferator-activated receptor gamma (PPARγ) regulates multiple pathways involved in the pathogenesis of obesity and atherosclerosis. Here, we evaluated the therapeutic potential of GQ-177, a new thiazolidinedione, on diet-induced obesity and atherosclerosis. The intermolecular interaction between PPARγ and GQ-177 was examined by virtual docking and PPAR activation was determined by reporter gene assay identifying GQ-177 as a partial and selective PPARγ agonist. For the evaluation of biological activity of GQ-177, low-density lipoprotein receptor-deficient (LDLr(-/-)) C57/BL6 mice were fed either a high fat diabetogenic diet (diet-induced obesity), or a high fat atherogenic diet, and treated with vehicle, GQ-177 (20mg/kg/day), pioglitazone (20mg/kg/day, diet-induced obesity model) or rosiglitazone (15mg/kg/day, atherosclerosis model) for 28 days. In diet-induced obesity mice, GQ-177 improved insulin sensitivity and lipid profile, increased plasma adiponectin and GLUT4 mRNA in adipose tissue, without affecting body weight, food consumption, fat accumulation and bone density. Moreover, GQ-177 enhanced hepatic mRNA levels of proteins involved in lipid metabolism. In the atherosclerosis mice, GQ-177 inhibited atherosclerotic lesion progression, increased plasma HDL and mRNA levels of PPARγ and ATP-binding cassette A1 in atherosclerotic lesions. GQ-177 acts as a partial PPARγ agonist that improves obesity-associated insulin resistance and dyslipidemia with atheroprotective effects in LDLr(-/-) mice., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The present work reports the synthesis and evaluation of the antitumour and immunomodulatory properties of new phthalimides derivatives designed to explore molecular hybridization and bioisosterism approaches between thalidomide, thiosemicarbazone, thiazolidinone and thiazole series. Twenty-seven new molecules were assessed for their immunosuppressive effect toward TNFα, IFNγ, IL-2 and IL-6 production and antiproliferative activity. The best activity profile was observed for the (6a-f) series, which presents phthalyl and thiazolidinone groups., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The present work reports on the synthesis, anti-Trypanosoma cruzi activities and docking studies of a novel series of 2-(pyridin-2-yl)-1,3-thiazoles derived from 2-pyridine thiosemicarbazone. The majority of these compounds are potent cruzain inhibitors and showed excellent inhibition on the trypomastigote form of the parasite, and the resulting structure-activity relationships are discussed. Together, these data present a novel series of thiazolyl hydrazones with potential effects against Chagas disease and they could be important leads in continuing development against Chagas disease., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

In this article, we describe that mononuclear complexes composed of (5-chloro-2-hydroxybenzylidene)aminobenzenesulfonamides (L1-3) of general formula (L2(M)2H2O, where M is Co, Cu, Zn, Ni or Mn) reduced epimastigote proliferation and were found cidal for trypomastigotes of Trypanosoma cruzi Y strain. Complexes C5 and C11 have IC50 of 2.7 ± 0.27 and 4.8 ± 0.47 µM, respectively, for trypomastigotes, when the positive control Nifurtimox, which is also an approved drug for Chagas disease, showed IC50 of 2.7 ± 0.25 µM. We tested whether these complexes inhibit the enzyme T. cruzi trypanothione reductase or acting as DNA binders. While none of these complexes inhibited trypanothione reductase, we observed some degree of DNA binding, albeit less pronounced than observed for cisplatin in this assay. Unfortunately, most of these complexes were also toxic for mouse splenocytes. Along with the present studies, we discuss a number of interesting structure-activity relationships and chemical features for these metal complexes, including computational calculations.

Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti-Trypanosoma cruzi thiazolidinones (4 a-p). (2-[2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 h) and (2-[2-phenoxy-1-(4-phenylphenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 μM, while they did not display host cell toxicity up to 200 μM. Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti-T. cruzi thiazolidinones (4 a-p) led to the identification of compounds with enhanced potency and selectivity compared to first-generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Mammalian natriuretic peptides (NPs) have been extensively investigated for use as therapeutic agents in the treatment of cardiovascular diseases. Here, we describe the isolation, sequencing and tridimensional homology modeling of the first C-type natriuretic peptide isolated from scorpion venom. In addition, its effects on the renal function of rats and on the mRNA expression of natriuretic peptide receptors in the kidneys are delineated. Fractionation of Tityus serrulatus venom using chromatographic techniques yielded a peptide with a molecular mass of 2190.64 Da, which exhibited the pattern of disulfide bridges that is characteristic of a C-type NP (TsNP, T. serrulatus Natriuretic Peptide). In the isolated perfused rat kidney assay, treatment with two concentrations of TsNP (0.03 and 0.1 μg/mL) increased the perfusion pressure, glomerular filtration rate and urinary flow. After 60 min of treatment at both concentrations, the percentages of sodium, potassium and chloride transport were decreased, and the urinary cGMP concentration was elevated. Natriuretic peptide receptor-A (NPR-A) mRNA expression was down regulated in the kidneys treated with both concentrations of TsNP, whereas NPR-B, NPR-C and CG-C mRNAs were up regulated at the 0.1 μg/mL concentration. In conclusion, this work describes the isolation and modeling of the first natriuretic peptide isolated from scorpion venom. In addition, examinations of the renal actions of TsNP indicate that its effects may be related to the activation of NPR-B, NPR-C and GC-C., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The compound (5Z)-5-[(5-bromo-1H-indol-3-yl)methylene]-3-(4-chlorobenzyl)-thiazolidine-2,4-dione (LYSO-7) was synthesised in order to obtain a new type of anti-inflammatory drug, designed with hybrid features to inhibit cyclooxygenase (COX) and also to activate peroxisome proliferator-activated receptor (PPAR). Results obtained from docking (in silico) studies corroborated with experimental data, showing the potential affinity between the studied ligand and targets. The specificity of LYSO-7 for COX-enzymes was detected by the inhibition of COX-1 and COX-2 activities by 30% and 20%, respectively. In transactivation reporter gene assays LYSO-07 showed a pan partial agonist effect on the three PPAR subtypes (PPARγ, PPARα and PPARβ/δ). The agonist action on PPARγ was also observed by a pharmacological approach, as the reduction in the Escherichia coli lipopolysaccharide (LPS)-induced interleukin 1 beta (IL-1β) secretion and nitric oxide (NO) production by mouse neutrophils was blocked by GW9962, a specific PPARγ antagonist. Additionally, the in vivo effect was measured by reduced carrageenan-induced neutrophil influx into the subcutaneous tissue of mice. Taken together, these data show that LYSO-7 displays a potent in vivo anti-inflammatory effect during the innate acute response, which is dependent on its associated COX inhibitory activities and PPAR activation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.

LPSF/AC04 (5Z)-[5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione] is an acridine-based derivative, part of a series of new anticancer agents synthesized for the purpose of developing more effective and less toxic anticancer drugs. However, the use of LPSF/AC04 is limited due to its low solubility in aqueous solutions. To overcome this problem, we investigated the interaction of LPSF/AC04 with hydroxypropyl-β-cyclodextrin (HP-β-CyD) and hydroxypropyl-γ-cyclodextrin (HP-γ-CyD) in inclusion complexes and determine which of the complexes formed presents the most significant interactions. In this paper, we report the physical characterization of the LPSF/AC04-HP-CyD inclusion complexes by thermogravimetric analysis, differential scanning calorimetry, infrared spectroscopy absorption, Raman spectroscopy, (1)HNMR, scanning electron microscopy, and by molecular modeling approaches. In addition, we verified that HP-β-CyD complexation enhances the aqueous solubility of LPSF/AC04, and a significant increase in the antiproliferative activity of LPSF/AC04 against cell lines can be achieved by the encapsulation into liposomes. These findings showed that the nanoencapsulation of LPSF/AC04 and LPSF/AC04-HP-CyD inclusion complexes in liposomes leads to improved drug penetration into the cells and, as a result, an enhancement of cytotoxic activity. Further in vivo studies comparing free and encapsulated LPSF/AC04 will be undertaken to support this investigation.

Background: Harpalycin 2 (HP-2) is an isoflavone isolated from the leaves of Harpalyce brasiliana Benth., a snakeroot found in northeast region of Brazil and used in folk medicine to treat snakebite. Its leaves are said to be anti-inflammatory. Secretory phospholipases A2 are important toxins found in snake venom and are structurally related to those found in inflammatory conditions in mammals, as in arthritis and atherosclerosis, and for this reason can be valuable tools for searching new anti-phospholipase A2 drugs., Methods: HP-2 and piratoxin-III (PrTX-III) were purified through chromatographic techniques. The effect of HP-2 in the enzymatic activity of PrTX-III was carried out using 4-nitro-3-octanoyloxy-benzoic acid as the substrate. PrTX-III induced platelet aggregation was inhibited by HP-2 when compared to aristolochic acid and p-bromophenacyl bromide (p-BPB). In an attempt to elucidate how HP-2 interacts with PrTX-III, mass spectrometry, circular dichroism and intrinsic fluorescence analysis were performed. Docking scores of the ligands (HP-2, aristolochic acid and p-BPB) using PrTX-III as target were also calculated., Results: HP-2 inhibited the enzymatic activity of PrTX-III (IC50 11.34 ± 0.28 μg/mL) although it did not form a stable chemical complex in the active site, since mass spectrometry measurements showed no difference between native (13,837.34 Da) and HP-2 treated PrTX-III (13,856.12 Da). A structural analysis of PrTX-III after treatment with HP-2 showed a decrease in dimerization and a slight protein unfolding. In the platelet aggregation assay, HP-2 previously incubated with PrTX-III inhibited the aggregation when compared with untreated protein. PrTX-III chemical treated with aristolochic acid and p-BPB, two standard PLA2 inhibitors, showed low inhibitory effects when compared with the HP-2 treatment. Docking scores corroborated these results, showing higher affinity of HP-2 for the PrTX-III target (PDB code: 1GMZ) than aristolochic acid and p-BPB. HP-2 previous incubated with the platelets inhibits the aggregation induced by untreated PrTX-III as well as arachidonic acid., Conclusion: HP-2 changes the structure of PrTX-III, inhibiting the enzymatic activity of this enzyme. In addition, PrTX-III platelet aggregant activity was inhibited by treatment with HP-2, p-BPB and aristolochic acid, and these results were corroborated by docking scores.

Secretory phospholipases A(2) (sPLA(2)) exert proinflammatory actions through lipid mediators. These enzymes have been found to be elevated in many inflammatory disorders such as rheumatoid arthritis, sepsis, and atherosclerosis. The aim of this study was to evaluate the effect of harpalycin 2 (Har2), an isoflavone isolated from Harpalyce brasiliana Benth., in the enzymatic, edematogenic, and myotoxic activities of sPLA(2) from Bothrops pirajai, Crotalus durissus terrificus, Apis mellifera, and Naja naja venoms. Har2 inhibits all sPLA(2) tested. PrTX-III (B. pirajai venom) was inhibited at about 58.7%, Cdt F15 (C. d. terrificus venom) at 78.8%, Apis (from bee venom) at 87.7%, and Naja (N. naja venom) at 88.1%. Edema induced by exogenous sPLA(2) administration performed in mice paws showed significant inhibition by Har2 at the initial step. In addition, Har2 also inhibited the myotoxic activity of these sPLA(2)s. In order to understand how Har2 interacts with these enzymes, docking calculations were made, indicating that the residues His48 and Asp49 in the active site of these enzymes interacted powerfully with Har2 through hydrogen bonds. These data pointed to a possible anti-inflammatory activity of Har2 through sPLA(2) inhibition.

The aim of this study was to encapsulate lapachone (β-lap) or inclusion complex (β-lap:HPβ-CD) in liposomes and to evaluate their physicochemical characteristics. In addition, the investigation of the main aspects of the interaction between β-lap and 2-hydroxypropyl-β-cyclodextrin (HPβ-CD), using both experimental and molecular modeling approaches was discussed. Furthermore, the in vitro drug release kinetics was evaluated. First, a phase solubility study of β-lap in HPβ-CD was performed and the β-lap:HPβ-CD was prepared by the freeze-drying technique. A 302-fold increase of solubility was achieved for β-lap in HPβ-CD solution with a constant of association K(1:1) of 961 M(-1) and a complexation efficiency of β-lap of 0.1538. (1)H NMR, TG, DSC, IR, Raman and SEM indicated a change in the molecular environment of β-lap in the inclusion complex. Molecular modeling confirms these results suggesting that β-lap was included in the cavity of HPβ-CD, with an intermolecular interaction energy of -23.67 kJ mol(-1). β-lap:HPβ-CD and β-lap-loaded liposomes presented encapsulation efficiencies of 93% and 97%, respectively. The kinetic rate constants of 183.95±1.82 μg/h and 216.25±2.34 μg/h were calculated for β-lap and β-lap:HPβ-CD-loaded liposomes, respectively. In conclusion, molecular modeling elucidates the formation of the inclusion complex, stabilized through hydrogen bonds, and the encapsulation of β-lap and β-lap:HPβ-CD into liposomes could provide an alternative means leading eventually to its use in cancer research., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The present study investigates the release mechanism of benznidazole (BNZ) in solid dispersions with polyethylene glycol 6000 (PEG 6000) and polyvinylpirrolydone K-30 (PVP K-30), with a view to observing the increase in solubility of BNZ in water in the presence of these two hydrophilic polymers. The interaction of BNZ with the polymers was evaluated using scanning electron microscopy, Fourier-transformation infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and in vitro dissolution tests, and a theoretical study of molecular modeling was also carried out. The drug-polymer interaction was studied trough molecular modeling, using density functional theory with the B3LYP exchange correlation function. The corrected interaction energies were calculated to be -20.9 kJ/mol with PVP and -6.6 kJ/mol with PEG. The experimental and theoretical results indicate that a powerful interaction occurred between BNZ and the polymers, which was especially strong in the case of PVP, and that this interaction contributed to improvement of BNZ solubility., (Copyright © 2011 Wiley-Liss, Inc.)

Solid dispersions have been used as a strategy to improve the solubility, dissolution rate, and bioavailability of poor water-soluble drugs. The increase of the dissolution rate presented by (5Z)-3-(4-chloro-benzyl)-5-(4-nitro-benzylidene)-imidazolidine-2,4-dione (LPSF/FZ4) from the solid dispersions is related to the existence of intermolecular interactions of hydrogen bond type (>N-H···O<) between the amide group (>N-H) of the LPSF/FZ4 and the ether group (-O-) of the polyethyleneglycol polymer, or the carbonyl (C=O) of the polyvinylpyrrolidone polymer (PVP). The intensity of these interactions is directly reflected in the morphology acquired by LPSF/FZ4 in these systems, where a new solid phase, in the form of amorphous aggregates of irregular size, was identified through scanning electron microscopy and confirmed in the characterizations achieved using X-ray diffraction and thermal analysis of DSC. The solid dispersions with the polymer PVP, in higher concentrations, were revealed to be the best option to be used in the formulations of LPSF/FZ4 in both theoretical and experimental studies., (© 2011 American Association of Pharmaceutical Scientists)

As polyphenolic compounds isolated from plants extracts, flavonoids have been applied to various pharmaceutical uses in recent decades due to their anti-inflammatory, cancer preventive, and cardiovascular protective activities. In this study, we evaluated the effects of the flavonoid quercetin on Crotalus durissus terrificus secretory phospholipase A2 (sPLA2), an important protein involved in the release of arachidonic acid from phospholipid membranes. The protein was chemically modified by treatment with quercetin, which resulted in modifications in the secondary structure as evidenced through circular dichroism. In addition, quercetin was able to inhibit the enzymatic activity and some pharmacological activities of sPLA2, including its antibacterial activity, its ability to induce platelet aggregation, and its myotoxicity by approximately 40%, but was not able to reduce the inflammatory and neurotoxic activities of sPLA2. These results suggest the existence of two pharmacological sites in the protein, one that is correlated with the enzymatic site and another that is distinct from it. We also performed molecular docking to better understand the possible interactions between quercetin and sPLA2. Our docking data showed the existence of hydrogen-bonded, polar interactions and hydrophobic interactions, suggesting that other flavonoids with similar structures could bind to sPLA2. Further research is warranted to investigate the potential use of flavonoids as sPLA2 inhibitors., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Thiazolidinediones (TZDs) are a class of drugs used for treatment of type 2 diabetes. However, the therapy with currently available TDZs (e.g. rosiglitazone) is associated with important side effects, such as edema and weight gain, suggesting that the investigation of alternative TZDs with better pharmacological properties is warranted. In this study, we investigated both anti-inflammatory and antioxidant properties of a new chemically modified TZD, the arylidene-thiazolidinedione 5-(4-methanesulfonyl-benzylidene)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione (SF23), and compared the results to those obtained with rosiglitazone. We found that our SF23 displays a weaker affinity for PPARγ, up-regulating in a lower magnitude the expression of both PPARγ and CD36 compared to rosiglitazone. In lipopolysaccharide (LPS)-stimulated macrophages, SF23 decreased nitrite production and attenuated the mRNA expression of both iNOS and COX-2. These anti-inflammatory effects were comparable to those obtained with rosiglitazone. Interestingly, SF23, but not rosiglitazone, prevented LPS-induced mitochondrial membrane hyperpolarization, apoptosis, reactive oxygen species (ROS) generation, and the expression of NADPH oxidase subunits, Nox1 and Nox2. In addition, in macrophages from Nrf2⁻/⁻ mice, SF23 protected against LPSinduced cellular death and ROS production, whereas rosiglitazone was only able to protect normal Nrf2⁺/⁺ cells against oxidative injury, suggesting that, unlike rosiglitazone, the antioxidant activity of SF23 might be Nrf2-independent. Finally, in macrophages exposed to high concentrations of glucose, SF23 induced significant increases in the mRNA expression of glucose transporters, insulin receptor substrate and mitoNEET. Altogether, our data indicate that our new chemically modified TDZ displays similar anti-inflammatory properties, but superior antioxidant effects on the LPS-stimulated macrophages compared to rosiglitazone.

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., (Copyright © 2010. Published by Elsevier Ltd.)

Eight new 5-arylidene-3-benzyl-thiazolidine-2,4-diones with halide groups on their benzyl rings were synthesized and assayed in vivo to investigate their anti-inflammatory activities. These compounds showed considerable biological efficacy when compared to rosiglitazone, a potent and well-known agonist of PPARgamma, which was used as a reference drug. This suggests that the substituted 5-arylidene and 3-benzylidene groups play important roles in the anti-inflammatory properties of this class of compounds. Docking studies with these compounds indicated that they exhibit specific interactions with key residues located in the site of the PPARgamma structure, which corroborates the hypothesis that these molecules are potential ligands of PPARgamma. In addition, competition binding assays showed that four of these compounds bound directly to the ligand-binding domain of PPARgamma, with reduced affinity when compared to rosiglitazone. An important trend was observed between the docking scores and the anti-inflammatory activities of this set of molecules. The analysis of the docking results, which takes into account the hydrophilic and hydrophobic interactions between the ligands and the target, explained why the 3-(2-bromo-benzyl)-5-(4-methanesulfonyl-benzylidene)-thiazolidine-2,4-dione compound had the best activity and the best docking score. Almost all of the stronger hydrophilic interactions occurred between the substituted 5-arylidene group of this compound and the residues of the binding site.

A significant number of drugs and drug candidates in clinical development are halogenated structures. For a long time, insertion of halogen atoms on hit or lead compounds was predominantly performed to exploit their steric effects, through the ability of these bulk atoms to occupy the binding site of molecular targets. However, halogens in drug - target complexes influence several processes rather than steric aspects alone. For example, the formation of halogen bonds in ligand-target complexes is now recognized as a kind of intermolecular interaction that favorably contributes to the stability of ligand-target complexes. This paper is aimed at introducing the fascinating versatility of halogen atoms. It starts summarizing the prevalence of halogenated drugs and their structural and pharmacological features. Next, we discuss the identification and prediction of halogen bonds in protein-ligand complexes, and how these bonds should be exploited. Interesting results of halogen insertions during the processes of hit-to-lead or lead-to-drug conversions are also detailed. Polyhalogenated anesthetics and protein kinase inhibitors that bear halogens are analyzed as cases studies. Thereby, this review serves as one guide for the virtual screening of libraries containing halogenated compounds and may be a source of inspiration for the medicinal chemists.

Although more complex than usually described, the anticancer action mechanism of cisplatin is based on binding to DNA. Following this line of reasoning, most the metal-based compounds discovered soon after cisplatin were designed to acting as DNA-binding agents and their pharmacological properties were thought to be correlated with this mechanism. Apart from the DNA structure, a significant number of proteins and biochemical pathways have been described as drug targets for metal-based compounds. This paper is therefore aimed at discussing the most recent findings on the medicinal chemistry of metal-based drugs. It starts illustrating the design concept behind the bioinorganic chemistry of anticancer complexes. Anticancer metallic compounds that inhibit the protein kinases are concisely discussed as a case study. The accuracy and limitations of molecular docking programs currently available to predict the binding mode of metallic complexes in molecular targets are further discussed. Finally, the advantages and disadvantages of different in vitro screenings are briefly commented.

A theoretical study is presented with the aim to investigate the molecular properties of intermolecular complexes formed by the monomeric units of polyvinylpyrrolidone (PVP) or polyethyleneglycol (PEG) polymers and a set of four imidazolidine (hydantoine) derivatives. The substitution of the carbonyl groups for thiocarbonyl in the hydantoin scaffold was taken into account when analyzing the effect of the hydrogen bonds on imidazolidine derivatives. B3LYP/6-31G(d,p) calculations and topological integrations derived from the quantum theory of atoms in molecules (QTAIM) were applied with the purpose of examining the N-H···O hydrogen bond strengths formed between the amide group of the hydantoine ring and the oxygen atoms of PVP and PEG polymers. The effects caused by the N-H···O interaction fit the typical evidence for hydrogen bonds, which includes a variation in the stretch frequencies of the N-H bonds. These frequencies were identified as being vibrational red-shifts because their values decreased. Although the values of such calculated interaction energies are between 12 and 33 kJ mol(-1), secondary intermolecular interactions were also identified. One of these secondary interactions is formed through the interaction of the benzyl hydrogen atoms with the oxygen atoms of the PVP and PEG structures. As such, we have analyzed the stretch frequencies on the C-H bonds of the benzyl groups, and blue-shifts were identified on these bonds. In this sense, the intermolecular systems formed by hydantoine derivatives and PVP/PEG monomers were characterized as a mix of red-shifting and blue-shifting hydrogen-bonded complexes.

The N-alkylated derivatives from nitrofurazone were synthesised and evaluated in vitro for their efficacy as antimicrobial agents against representative strains, including methicillin-resistant Staphylococcus aureus (MRSA). The derivative 2a demonstrated greater activity than the prototype and was comparable to currently used antimicrobial drugs.

New arylidene-thiazolidinediones (ATZDs) were synthesized and evaluated in the alloxan-induced hyperglycemia mice model. The molecular target taken into consideration is the nuclear PPAR-gamma whose crystallographic structure is available on the PDB database as 2PRG. Thus the hypoglycemic and hypolipidemic activities of compounds were compared with the result of their docking after removal of the co-crystallized ligand present in the 2PRG structure. Molecular modeling studies were carried out using the Autodock 3.0.5 and ADT 1.1 programs.

Research in recent years has demonstrated that the Trypanosoma cruzi cysteine protease cruzain (TCC) is a valid chemotherapeutic target. Herein we describe a small library of aryl-4-oxothiazolylhydrazones that have been tested in assays against T. cruzi cell cultures. The docking studies carried out suggest that these compounds are potential ligands for the TCC enzyme. The most promising compound of this series, N-(4-oxo-5-ethyl-2'-thiazolin-2-yl)-N'-phenylthio-(Z)-ethylidenehydrazone (6 f), was shown to be very active at non-cytotoxic concentrations in in vitro assays with mammalian cells and has a potency comparable with reference drugs such as nifurtimox (Nfx) and benznidazole (Bdz).

A novel series of thiosemicarbazone and aminoacyl-thiazolidones derivatives were synthesized. Their structure suggests that these compounds could have anti-Trypanosoma cruzi activity. Biological evaluation indicates that some of these compounds are able to inhibit the growth of T. cruzi in concentrations non-cytotoxic to mammalian cells. Docking studies were carried out in order to investigate the binding pattern of these compounds for the T. cruzi cruzain (TCC) protein, and these showed a significant correlation with experimental data.

An unambiguous, fully ab initio and automated technique denoted AIPAR ("ab initio parametrization") implemented in the SJBR program has been proposed to yield intermolecular interaction potentials between polar molecules and water. The AIPAR procedure has been applied to several organic molecules covering a wide range of structure and functional groups, namely methanol, acetone (propanone), methanethiol (methyl mercaptan), imidazole (1,3-diazole), oxazole and furan. The AIPAR-derived sets of parameters compare well with the empirical OPLS ones, mainly when the all-atoms model is employed in the OPLS procedure. Monte Carlo simulations were performed for an aqueous solution of methanol and for an equimolar binary mixture methanol-water using the AIPAR and OPLS parameters. The thermodynamic and geometric results obtained with the parameters obtained with the AIPAR procedure compare favorably with the OPLS simulations, even for the binary mixture, demonstrating the precision, robustness and transferability of the parameters obtained with the AIPAR procedure.

The multivariate chemometric techniques two level factorial design (TLFD) and principal component analysis (PCA) were used to investigate the TIP4P model potential behavior with respect to perturbations on all intermolecular interaction parameters. The effects of these perturbations were calculated for the enthalpy of vaporization, the density, the first maximum of the radial distribution functions of the O-H and O-O pairs, and the second maximum of the radial distribution function of the O-H pair obtained from Monte Carlo simulations of liquid water at 25 degrees C. The principal effects were quantified and rationalized in terms of the pair-wise interaction potential of the TIP4P model. They also corroborate previously published sensitivity analysis results using molecular dynamics and other model potentials. In addition, significant interaction effects between some parameters of the TIP4P model potential were observed and quantified, which hardly could be obtained without such a statistic approach. These interaction effects are very regular and systematic, and their behavior has not been encountered in other chemometric studies and cannot be rationalized in terms of the functional form of the pair-wise potential., (Copyright 2003 Wiley Periodicals, Inc. J Comput Chem 24: 973-981, 2003)

We have carried out a combined experimental and theoretical study of the molecular structure of the MoO(O(2))(2)(OPy)(H(2)O) coordination compound using X-ray crystallography and DFT-B3LYP computational method, respectively. The MoO(O(2))(2)(OPy)(H(2)O) complex crystallizes in the orthorhombic space group Pmna with Z = 4, a = 6.9001(9) A, b = 8.0471(1) A, c = 16.227(2) A, V = 901.0(2) A(3), and the X-ray data analysis yields a bipyramidal-pentagonal coordination polyhedron for the Mo atom. The pyridine N-oxide (OPy) ligand occupies the equatorial position, with the oxygen atom of this ligand being located in the same plane as the four peroxo oxygen atoms. The H(2)O ligand is situated trans to the oxo group, forming intermolecular hydrogen bonds with peroxo groups belonging to two adjacent complexes. In our theoretical approach these intermolecular interactions were taken into account by including two methanol molecules which form hydrogen bonds with the water ligand leading to a good agreement between the calculated and the experimental geometry. Our results suggest that it is necessary to take into account the presence of these interactions in order to reconcile the theoretical results to the experimental data, in particular the distance between Mo and the oxygen of water ligand. These results seem to be a general feature for analogous bis-peroxo complexes that have been reported in the literature.