Helena C. Castro

Leishmaniasis treatment—a challenge that remains: a review

Leishmaniasis is a disease caused by flagellate protozoan Leishmania spp. and represents an emergent illness with high morbidity and mortality in the tropics and subtropics. Since the discovery of the first drugs for Leishmaniasis treatment (i.e., pentavalent antimonials), until the current days, the search for substances with antileishmanial activity, without toxic effects, and able to overcome the emergence of drug resistant strains still remains as the current goal. This article reports the development of new chemotherapies through the rational design of new drugs, the use of products derived from microorganisms and plants, and treatments related to immunity as new alternatives for the chemotherapy of leishmaniasis.

Antiplatelet properties of novel N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone derivatives

This paper describes the design, synthesis and pharmacological evaluation of new N-acylhydrazone (NAH) compounds, belonging to the N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone class (2a-p). Classical heteroaromatic ring bioisosterism strategies were applied to the previously reported N-phenylpyrazolyl-4-acylhydrazone derivative 1, elected as lead-compound due to its important anti-aggregating profile on arachidonic acid induced platelet aggregation (IC(50)=24+/-0.5 micro M), from which emerge this new series 2. These new compounds 2a-p were readily synthesized, characterized and tested on platelet aggregation assays induced by collagen (5 micro g/mL), ADP (5 micro M) and arachidonic acid (100 micro M) in rabbit citrated platelet-rich plasma. Compounds 2b, 2d, and 2h were found to be the most potent, exhibiting a significant antiplatelet activity on arachidonic acid- and collagen-induced platelet aggregation. In addition, these new antiplatelet agents are free of gastric ulcerogenic effect and presented discrete anti-inflammatory and analgesic properties. The N-para-chlorophenyltriazolyl-4-acylhydrazone compound 2h produced the highest inhibitory effect on collagen (IC(50)=21.6+/-0.4 micro M) and arachidonic acid-induced platelet aggregation (IC(50)=2.2+/-0.06 micro M), suggesting that the nature of the substituent on the phenyl ring of the N-heteroaromatic system of NAH moiety may be an important structural requirement for the improvement of antiplatelet activity, in comparison with lead-series 1.

Snake venom thrombin-like enzymes: from reptilase to now.

The snake venom thrombin-like enzymes (SVTLEs) comprise a number of serine proteases functionally and structurally related to thrombin. Until recently, only nine complete sequences of this subgroup of the serine protease family were known. Over the past 5 years, the primary structure of several SVTLEs has been characterized, and now this family includes several members. Of particular interest is their possible use in pathologies such as thrombosis. The aim of the present review is to summarize the state of the art concerning the evolutionary, structural and biological features of the SVTLEs.

Synthesis, HIV-RT inhibitory activity and SAR of 1-benzyl-1H-1,2,3-triazole derivatives of carbohydrates.

This paper describes the synthesis of several 1-benzyl-1H-1,2,3-triazoles attached to different carbohydrate templates and their in vitro inhibitory profile against HIV-1 reverse transcriptase. In addition a theoretical comparison of the most active compounds with other classical antivirals was also performed. Our results showed 2a, 2d and 2g as the most active compounds that inhibited the HIV-1 reverse transcriptase catalytic activity with cytotoxicity lower than AZT and SI higher than DDC and DDI. The overall theoretical analysis of the molecular descriptors of 2a, 2d and 2g revealed that their HOMO energy is similar to other antivirals in use (AZT, DDC, DDI and 3TC) and together with the volume may contribute for the biological profile as they may allow new interactions with the target. In fact the 1,2,3-triazole compounds presented more lipophilicity and higher molecular volume and weight than the antivirals studied, which suggested that these features might not only contribute for new interactions with the HIV-RT but also influence the specificity and consequently the low cytoxicity profile of these compounds. Thus these data point them as promising leading compounds for generating new anti-HIV-RT compounds.

Staphylococcus aureus: visitando uma cepa de importância hospitalar

Staphylococcus aureus is a bacterium from Gram-positive coccus group, which is part of the human microbiota. It may cause diseases that may vary from simple infections (i.e., pimples and furuncles) to severe infections, such as pneumonia, meningitis, endocarditis, toxic shock syndrome and septicemia, among others. This bacterium was one of the first bacteria affected by antibacterial agents, however, its ability of adaptation and resistance turns it into an important hospital and communitarian pathogenic species of great concern. In this article we will discuss some important points related to the S. aureus and the pathologies related to it to reinforce it as a target for the design of new antibiotics.

Synthesis, antichagasic in vitro evaluation, cytotoxicity assays, molecular modeling and SAR/QSAR studies of a 2-phenyl-3-(1-phenyl-1H-pyrazol-4-yl)-acrylic acid benzylidene-carbohydrazide series.

Chagas disease (American trypanosomiasis) is one of the most important parasitic diseases with serious social and economic impacts mainly on Latin America. This work reports the synthesis, in vitro trypanocidal evaluation, cytotoxicity assays, and molecular modeling and SAR/QSAR studies of a new series of N-phenylpyrazole benzylidene-carbohydrazides. The results pointed 6k (X=H, Y=p-NO2, pIC(50)=4.55 M) and 6l (X=F, Y=p-CN, pIC(50)=4.27 M) as the most potent derivatives compared to crystal violet (pIC(50)=3.77 M). The halogen-benzylidene-carbohydrazide presented the lowest potency whereas 6l showed the most promising profile with low toxicity (0% of cell death). The best equation from the 4D-QSAR analysis (Model 1) was able to explain 85% of the activity variability. The QSAR graphical representation revealed that bulky X-substituents decreased the potency whereas hydrophobic and hydrogen bond acceptor Y-substituents increased it.

Synthesis, antiplatelet and in silico evaluations of novel N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides

This paper describes the synthesis, antiplatelet and theoretical evaluations of 10 N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (2a-j). These compounds were synthesized, characterized and screened for their in vitro antiplatelet profile against human platelet aggregation using arachidonic acid, adrenaline and ADP as agonists. Among NAH derivatives 2a-j, the compounds 2a, 2c, 2e, 2g and 2h were the most promising molecules with significant antiplatelet activity.

Synthesis, antitubercular activity, and SAR study of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides

Tuberculosis treatment remains a challenge that requires new antitubercular agents due to the emergence of multidrug-resistant Mycobacterium strains. This paper describes the synthesis, the antitubercular activity and the theoretical analysis of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (8a-b, 8e-f, 8i-j and 8n-o) and new analogues (8c-d, 8g-h, 8l-m and 8p-q). These derivatives were synthesized in good yields and some of them showed a promising antitubercular profile. Interestingly the N-acylhydrazone (NAH) 8n was the most potent against the Mycobacterium tuberculosis H37Rv strain (MIC=2.5 μg/mL) similar to or better than the current drugs on the market. The theoretical structure-activity relationship study suggested that the presence of the furyl ring and the electronegative group (NO(2)) as well as low lipophilicity and small volume group at R position are important structural features for the antitubercular profile of these molecules. NMR spectra, IR spectra and elemental analyses of these substances are reported.

Synthesis, biological evaluation and SAR of sulfonamide 4-methoxychalcone derivatives with potential antileishmanial activity.

Despite clinical importance of leishmaniasis, an infectious disease that affects 12 thousand million people in 88 countries, the treatment is still unsatisfactory due to its limited efficacy, cost expensive and undesirable side effects. Aiming to develop new antileishmanial lead compounds, we used a rational approach to synthesize a new set of sulfonamide 4-methoxychalcone derivatives (3a-3i) and evaluate the sulfonamide and methoxy moieties as promising adding-groups to chalcones. For that purpose we tested this new set against Leishmania braziliensis promastigotes and intracellular amastigotes and determined its cell toxicity profile. Interestingly all compounds presented a concentration-dependent antileishmanial profile and the benzylamino derivative (3i) showed a biological activity better than pentamidine. None of these compounds affected Trypanosoma cruzi epimastigotes, which suggests a specific antileishmanial profile. The structure-activity analysis of these sulfonamide 4-methoxychalcone derivatives pointed the molecular volume, the HOMO density concentrated in the chalcone moiety and the conformational structure of the compounds as important structural and stereoelectronic features for the antileishmanial activity. In addition, these compounds also fulfilled Lipinski rule of 5 and presented druglikeness similar to antileishmanial drugs. Altogether these results point the sulfonamide 4-methoxychalcone derivatives as potential lead compounds for designing new candidates for leishmaniasis treatment.

Antibacterial profile against drug-resistant Staphylococcus epidermidis clinical strain and structure-activity relationship studies of 1H-pyrazolo(3,4-b)pyridine and thieno(2,3-b)pyridine derivatives

Antibacterial resistance is a complex problem that contributes to health and economic losses worldwide. The Staphylococcus epidermidis is an important nosocomial pathogen that affects immunocompromised patients or those with indwelling devices. Currently, there are several resistant strains including S. epidermidis that became an important medical issue mainly in hospital environment. In this work, we report the biological and theoretical evaluations of a 4-(arylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acids series (1, 1a-m) and the comparison with a new isosteric ring nucleus series, 4-(arylamino)thieno[2,3-b]pyridine-5-carboxylic acids derivatives (2, 2a-m). Our results revealed the 1H-pyrazolo[3,4-b]pyridine derivatives significant antibacterial activity against a drug-resistant S. epidermidis clinical strain in contrast to the thieno[2,3-b]pyridine series. The minimal inhibitory concentration (MIC) of the most active derivatives (1a, 1c, 1e, and 1f) against S. epidermidis was similar to that of oxacillin and twofold better than chloramphenicol. Interestingly, the position of the functional groups has a great impact on the activity as observed in our structure-activity relationship (SAR) study. The SAR of 1H-pyrazolo[3,4-b]pyridine derivatives shows that the highest inhibitory activity is observed when the meta position is occupied by electronegative substituents. The molecular modeling analysis of frontier molecular orbitals revealed that the LUMO density is less intense in meta than in ortho and para positions for both series (1 and 2), whereas HOMO density is overconcentrated in 1H-pyrazolo[3,4-b]pyridine ring nucleus compared to the thieno[2,3-b]pyridine system. The most active derivatives of series 1 were submitted to in silico ADMET screening, which confirmed these compounds as potential antibacterial candidates.