Synthesis, biological evaluation and mechanism of action of benzothiazole derivatives with aromatic hydrazone moiety, a new class of antileishmanial compounds.

Leishmaniasis is a disease caused by protozoa Leishmania spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of L. amazonensis, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC50 values of 28.86 and 7.70 µM, against promastigotes and amastigotes of L. amazonensis, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies.

Synthesis, Solvatochromism and Estimation of Ground and Excited State Dipole Moments of Silylated Benzothiazole Dyes.

Dyes derived from benzothiazoles are an important class of heterocycles which have remarkable photophysical properties. New photoluminescent 2-phenylbenzothiazole derivatives containing different functional groups were synthesized in high yields and used for silylated derivatives synthesis. The new photoactive compounds were fully characterized and their photophysical properties were investigated. The absorption and fluorescence spectra of the benzothiazoles and their silylated derivatives were evaluated in a series of organic solvents. The results showed that the benzothiazoles present absorption in the ultraviolet range and emission in the blue region with moderate quantum yields and large Stokes shift. The solvatochromism of these compounds was investigated by using Lippert and ET(30) Dimroth-Reichardt empirical solvent polarity scales. The dipole moments obtained by Bakshiev and Kawaski-Chamma-Viallet equations revealed that the excited states were more polar than the ground states.

Riluzole, a Derivative of Benzothiazole as a Potential Anti-Amoebic Agent against Entamoeba histolytica.

Amoebiasis is produced by the parasite Entamoeba histolytica; this disease affects millions of people throughout the world who may suffer from amoebic colitis or amoebic liver abscess. Metronidazole is used to treat this protozoan, but it causes important adverse effects that limit its use. Studies have shown that riluzole has demonstrated activity against some parasites. Thus, the present study aimed, for the first time, to demonstrate the in vitro and in silico anti-amoebic activity of riluzole. In vitro, the results of Entamoeba histolytica trophozoites treated with IC50 (319.5 µM) of riluzole for 5 h showed (i) a decrease of 48.1% in amoeba viability, (ii) ultrastructural changes such as a loss of plasma membrane continuity and alterations in the nuclei followed by lysis, (iii) apoptosis-like cell death, (iv) the triggering of the production of reactive oxygen species and nitric oxide, and (v) the downregulation of amoebic antioxidant enzyme gene expression. Interestingly, docking studies have indicated that riluzole presented a higher affinity than metronidazole for the antioxidant enzymes thioredoxin, thioredoxin reductase, rubrerythrin, and peroxiredoxin of Entamoeba histolytica, which are considered as possible candidates of molecular targets. Our results suggest that riluzole could be an alternative treatment against Entamoeba histolytica. Future studies should be conducted to analyze the in vivo riluzole anti-amoebic effect on the resolution of amebic liver abscess in a susceptible model, as this will contribute to developing new therapeutic agents with anti-amoebic activity.

A Green Approach to 2-Substituted Benzo- and Naphthothiazoles via N-bromosuccinimide/Bromide-Mediated C(aryl)-S Bond Formation.

2-Substituted benzo- and naphthothiazoles have been conveniently prepared from the intramolecular cyclization of phenylthioureas and activated thiobenzanilides or the coupling of isothiocyanates with amines under mild conditions using N-bromosuccinimide/tetrabutylammonium bromide in 1,2-dimethoxyethane (DME) under ambient conditions. The reactions produce moderate to excellent yields with good functional group tolerance and avoid the use of harsh thermal conditions, corrosive reagents, halogenated solvents, toxic metal salts, and expensive metal catalysts, and are amenable to preparations on a gram-scale.

Phenylbenzothiazole derivatives: effects against a Trypanosoma cruzi infection and toxicological profiles.

Current treatments for Chagas disease have a limited impact during the chronic stage and trigger severe side effects. Treatments target Trypanosoma cruzi, the etiological agent of the disease. The aims of this study were to evaluate the trypanocidal activity of four 2-phenylbenzothiazole derivatives (BZT1-4) in vitro by using the infectious and non-infectious forms of T. cruzi (trypomastigotes and epimastigotes, respectively) and to test the most promising compound (BZT4) in vivo in mice. Additionally, the toxicological profile and possible neuronal damage were examined. In relation to trypomastigotes, BZT4 was more selective and effective than the reference drug (benznidazole) during this infective stage, apparently due to the synergistic action of the CF3 and COOH substituents in the molecule. During the first few hours post-administration of BZT4, parasitemia decreased by 40% in an in vivo model of short-term treatment, but parasite levels later returned to the basal state. In the long-term assessment, the compound did not produce a significant antiparasitic effect, only attaining a 30% reduction in parasitemia by day 20 with the dose of 16 mg/kg. The toxicity test was based on repeated dosing of BZT4 (administered orally) during 21 days, which did not cause liver damage. However, the compound altered the concentration of proteins and the proteinic profile of neuronal cells in vitro, perhaps leading to an effect on the central nervous system. Further research on the low trypanocidal activity in vivo compared to the better in vitro effect could possibly facilitate molecular redesign to improve trypanocidal activity.

Design, synthesis, molecular docking and in vitro evaluation of benzothiazole derivatives as 11ß-hydroxysteroid dehydrogenase type 1 inhibitors.

11-Beta hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regulates cortisol levels mainly in adipose, hepatic and brain tissues. There is a relationship between the high activity of this enzyme and the development of obesity and metabolic disorders. The inhibition of 11ß-HSD1 has been shown to attenuate the development of type 2 diabetes mellitus, insulin resistance, metabolic syndrome and other diseases mediated by excessive cortisol production. In this work, fifteen benzothiazole derivatives substituted with electron-withdrawing and electron-donating groups were designed to explore their affinity for 11ß-HSD1 using in silico methods. The results show that (E)-5-((benzo[d]thiazol-2-ylimino)(methylthio)methylamino)-2-hydroxybenzoic acid (C1) has good physicochemical properties and favorable interactions with 11ß-HSD1 through hydrogen bonding and hydrophobic interactions in the catalytic site formed by Y183, S170 and Y177. Furthermore, C1 was synthesized and evaluated in vitro and ex vivo using clobenzorex (CLX) as a reference drug in obese Zucker rats. The in vitro results showed that C1 was a better inhibitor of human 11ß-HSD1 than CLX. The ex vivo assay results demonstrated that C1 was capable of reducing 11ß-HSD1 overexpression in mesenteric adipose tissue. Therefore, C1 was able to decrease the activity and expression of 11ß-HSD1 better than CLX.

The Azoles in Pharmacochemistry: Perspectives on the Synthesis of New Compounds and Chemoinformatic Contributions.

Due to their versatile biological activity, Azoles are widely studied in pharmacochemistry. It is possible to use them in many applications and in studies aimed at discovering antiparasitic, antineoplastic, antiviral, antimicrobial compounds; and in the production of materials for treatment of varied pathologies. Based on their biological activity, our review presents several studies that involve this class of organic compounds. A bibliographic survey of this type can effectively contribute to pharmaceutical sciences, stimulating the discovery of new compounds, and structural improvements to biological profiles of interest. In this review, articles are discussed involving the synthesis of new compounds and chemoinformatic contributions. Current applications of azoles in both the pharmaceutical and agri-business sectors are well known, yet as this research highlights, azole compounds can also bring important contributions to the fight against many diseases. Among the heterocyclics, azoles are increasingly studied by research groups around the world for application against tuberculosis, HIV, fungal and bacterial infections; and against parasites such as leishmaniasis and trypanosomiasis. Our hope is that this work will help arouse the interest of research groups planning to develop new bioactives to fight against these and other diseases.

Exploring the structural landscape of 2-(thiophen-2-yl)-1,3-benzothiazole: high-Z' packing polymorphism and cocrystallization with calix[4]tube.

We report here for the first time a cocrystal of the so-called neutral calix[4]tube, which is two tail-to-tail-arranged and partially deprotonated tetrakis(carboxymethoxy)calix[4]arenes, including three sodium ions, with 2-(thiophen-2-yl)-1,3-benzothiazole, namely trisodium bis(carboxymethoxy)bis(carboxylatomethoxy)calix[4]arene tris(carboxymethoxy)(carboxylatomethoxy)calix[4]arene-2-(thiophen-2-yl)-1,3-benzothiazole-dimethyl sulfoxide-water (1/1/2/2), 3Na+·C36H30O122-·C36H31O12-·C11H7NS2·2C2H6OS·2H2O, which provides a new approach into the host-guest chemistry of inclusion complexes. Three packing polymorphs of the same benzothiazole with high Z' (one with Z' = 8 and two with Z' = 4) were also discovered in the course of our desired cocrystallization. The inspection of these polymorphs and a previously known polymorph with Z' = 2 revealed that Z' increases as the strength of intermolecular contacts decreases. Also, these results expand the frontier of invoking calixarenes as a host for nonsolvent small molecules, besides providing knowledge on the rare formation of high-Z' packing polymorphs of simple molecules, such as the target benzothiazole.

N-Myristoyltransferases as antileishmanial targets: a piggyback approach with benzoheterocyclic analogues

Leishmaniasis is one of the neglected diseases that remain in need for pharmacological alternatives. In this context, N-Myristoyltransferases (NMT) arise as interesting targets to explore since they are involved in the co/post-translational processing of peptides which are responsible for host cell invasion. Studies that consider these enzymes as targets point out the potential of benzoheterocyclic compounds as inhibitors of Candida albicans's N-myristoyltransferase. Here we applied a combination of comparative binding site analysis and molecular docking studies based on a Piggyback approach in the search for new Leishmania major NMT ligands. Our results revealed that NMT enzymes from both pathogens present enough structural similarity to allow extrapolation of the knowledge available from C. albicans studies to develop new L. major NMT inhibitors. Molecular docking studies with benzoheterocyclic analogues indicate the potential of benzothiazole derivatives as L. major NMT ligands, giving rise to a completely new class of chemical compounds to be explored in the development of antileishmanial drugs.

Small benzothiazole molecule induces apoptosis and prevents metastasis through DNA interaction and c-MYC gene supression in diffuse-type gastric adenocarcinoma cell line.

Chemo-resistance has been reported as a relevant barrier for the efficiency of gastric cancer treatment. Therefore, the development of effective and safe drugs for cancer chemotherapy is still a challenge. The purpose of this study was to evaluate the anticancer potential of (E)-2-(((2-(benzo[d]thiazo-2-yl)hydrazono)methyl)-4-nitrophenol) (AFN01) against gastric cancer cell lines. Our results showed promising anticancer activity against gastric cancer cells ACP-02 (IC50 = 1.0 µM) and mild activity against other cell lines including non-malignant gastric cell MNP-01 (IC50 = 3.4 µM). This compound significantly induced S phase cell cycle arrest, prevented cell migration and triggered apoptosis in a concentration-dependent manner. Moreover, AFN01 was significantly more genotoxic against tumoral cell ACP-02, when compared to non-malignant cells, such as MNP-01 and healthy peripheral mononuclear blood cells. AFN01 also synergistically interacts with doxorubicin suppressing cell proliferation and c-MYC gene expression in gastric cancer cell line model, with remarkable c-MYC overexpression. Although further pre-clinical and clinical studies are required to explore its safety and efficiency, AFN01 may represent a promising lead anticancer agent for the treatment of gastric cancer.

Green Synthesis of Potential Antifungal Agents: 2-Benzyl Substituted Thiobenzoazoles.

A series of benzyl-substituted thiobenzoazoles were synthesized by an environmentally friendly approach, to search for new antifungal agrochemicals. Compounds were prepared starting from 2-mercaptobenzoazoles, using KOH, benzyl halides, and water, resulting in a simple and ecological method. New antifungals were tested against a group of phytopathogenic fungi. Two compounds showed an interesting activity against Botrytis cinerea, Fusarium oxysporum, and Aspergillus spp.: 2-((4-(trifluoromethyl)benzyl)thio)benzo[d]thiazole, 3ac, and 2-((4-methylbenzyl)thio)benzo[d]thiazole, 3al. Thus, 3ac and 3al can be considered as broad spectrum antifungal agents. Furthermore, two new compounds, 2-((4-iodobenzyl)thio)benzo[d]thiazole, 3aj, and 2-(benzylthio)benzo[d]oxazole, 3ba, showed better inhibitory effect against Botrytis cinerea and Fusarium oxysporum when compared to the commercial fungicide Captan. Thus, 3aj and 3ba can be considered reduced-spectrum antifungals.

New platinum(II) complexes with benzo-thia-zole ligands.

Four new platinum(II) complexes, namely tetra-ethyl-ammonium tri-bromido-(2-methyl-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C8H7NS)] (1), tetra-ethyl-ammonium tri-bromido-(6-meth-oxy-2-methyl-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C9H9NOS)] (2), tetra-ethyl-ammonium tri-bromido-(2,5,6-trimethyl-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C10H11NS)] (3), and tetra-ethyl-ammonium tri-bromido-(2-methyl-5-nitro-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C8H6N2O2S)] (4), have been synthesized and structurally characterized by single-crystal X-ray diffraction techniques. These species are precursors of compounds with potential application in cancer chemotherapy. All four platinum(II) complexes adopt the expected square-planar coordination geometry, and the benzo-thia-zole ligand is engaged in bonding to the metal atom through the imine N atom (Pt-N). The Pt-N bond lengths are normal: 2.035 (5), 2.025 (4), 2.027 (5) and 2.041 (4) Šfor complexes 1, 2, 3 and 4, respectively. The benzo-thia-zole ligands are positioned out of the square plane, with dihedral angles ranging from 76.4 (4) to 88.1 (4)°. The NEt4 cation in 3 is disordered with 0.57/0.43 occupancies.

Excited-State Proton Transfer Can Tune the Color of Protein Fluorescent Markers.

We show by quantum mechanical/molecular mechanical (QM/MM) simulations that phenylbenzothiazoles undergoing an excited-state proton transfer (ESPT) can be used to probe protein binding sites. For 2-(2'-hydroxy-4'-aminophenyl)benzothiazole (HABT) bound to a tyrosine kinase, the absolute and relative intensities of the fluorescence bands arising from the enol and keto forms are found to be strongly dependent on the active-site conformation. The emission properties are tuned by hydrogen-bonding interactions of HABT with the neighboring amino acid T766 and with active-site water. The use of ESPT tuners opens the possibility of creating two-color fluorescent markers for protein binding sites, with potential applications in the detection of mutations in cancer cell lines.