Plínio Cunha Sathler

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.

Two novel defensin-encoding genes of the Chagas disease vector Triatoma brasiliensis (Reduviidae, Triatominae): gene expression and peptide-structure modeling.

Defensins are cysteine-rich peptides involved in the innate immunity of insects and many other organisms. In the present study, two novel defensin-encoding cDNAs and the respective genomic DNAs (def3 and def4) of Triatoma brasiliensis were identified and their tissue-specific and temporal expression was characterized. Both of the deduced mature peptides consisted of 43 amino acid residues and were highly similar to previously identified triatomine defensins (81.4-100%). Semi-quantitative RT-PCR data showed that def3 was constitutively expressed in the fat body and was induced in salivary glands and the small intestine at 5 and 3 days after feeding (daf), respectively. The def4 mRNA level was highly up-regulated in the stomach and fat-body tissues at 5 and 3 daf, respectively. The three-dimensional structures of these defensins were predicted using a homology modeling approach with Def-AAA, the defensin from Anopheles gambiae, as template (62-74% identity). A map of the electrostatic potential of these models revealed that, despite their similar folding patterns, mature Def2 and Def4 have a more cationic structure than is the case for Def1 and Def3. Such differences may orient the antimicrobial profile of these defensins against distinct targets in different organs of the insect.

In vitro and in vivo analysis of the antithrombotic and toxicological profile of new antiplatelets N-acylhydrazone derivatives and development of nanosystems: determination of novel NAH derivatives antiplatelet and nanotechnological approach.

BACKGROUND Cardiovascular diseases are the most frequent cause of morbidity and mortality worldwide. Among the most important cardiovascular diseases are atherothrombosis and venous thromboembolism that present platelet aggregation as a key event. Currently, the commercial antiplatelet agents display several undesirable effects, which prompt the search for new compounds with better therapeutic index, more efficient body distribution and mechanism. METHODS In this work we characterized in vivo and in vitro the antithrombotic and toxicological profiles of novel antiplatelet N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides derivatives also comparing them with aspirin. In addition we also analyzed the stability of the more active compound after encapsulation in PLGA or PCL nanoparticles and the release profile of these new nanosystems. RESULTS The biological results revealed not only the selective effect against arachidonic acid-induced platelet aggregation mainly for compounds 2c, 2e and 2h but also their in vivo active profile on thromboembolism pulmonary animal model with better survival rates (e.g. 82%) than aspirin (33%). The overall toxicological profile was determined by in vitro (MTT reduction tests, neutral red uptake in kidney VERO cells and hemolysis assays) and in vivo (pulmonary embolism) assays that pointed 2c as the most promising derivative with potential as a lead compound. By using the nanoprecipitation technique 2c was loaded into PLGA and PCL nanoparticles showing controlled release profile over 21days according to our drug release tests. CONCLUSION According to our results compound 2c is the most interesting derivative for further studies as it showed the best activity and toxicological profile also allowing the nanoencapsulation process. Thus 2c may assist in determining a new potential therapy with favorable pharmacokinetics for treatment of thrombotic disorders.

Human thromboxane synthase: comparative modeling and docking evaluation with the competitive inhibitors Dazoxiben and Ozagrel

Abstract Thromboxane synthase (TXAS) is a P450 epoxygenase that synthesizes thromboxane A2 (TXA2), a potent mediator of platelet aggregation, vasoconstriction and bronchoconstriction. This enzyme plays an important role in several human diseases, including myocardial infarction, stroke, septic shock, asthma and cancer. Despite of the increasing interest on developing TXAS inhibitors, the structure and activity of TXAS are still not totally elucidated. In this study, we used a comparative molecular modeling approach to construct a reliable model of TXAS and analyze its interactions with Dazoxiben and Ozagrel, two competitive inhibitors. Our results were compatible with experimental published data, showing feasible cation–π interaction between the iron atom of the heme group of TXAS and the basic nitrogen atom of the imidazolyl group of those inhibitors. In the absence of the experimental structure of thromboxane synthase, this freely available model may be useful for designing new antiplatelet drugs for diseases related with TXA2.

Preparation and Evaluation of a New Nano Pharmaceutical Excipients and drug Delivery System Based in Polyvinylpyrrolidone and Silicates

PURPOSE: This work describes the preparation of new nanocomposites based on lamellar silicates (AAM-alkyl ammonium montmorillonite) obtained by the intercalation of PVP K30 and glyceril monostearate. METHODS: By XRD, TGA and DSC analysis the AAM was characterized and its compactation characteristics, functionality and toxicity were also tested. The AAM/PVP K-30 and AAM/GME nanocomposite obtained were evaluated to identify the interlamellar spacing values by XRD diffratograms. Tablets were prepared using methyldopa and theophylline as model drugs and the dissolution tests were carried out in simulated gastric fluid and simulated enteric fluid. RESULTS: AAM showed a good compactability and compressibility characteristics for tablets preparation. The intercalation yields (approximately 25%) of the nanocomposites were efficient. The AAM/PVP K-30 nanocomposites were successfully tested as dissolution enhancers and sustained release matrixes. CONCLUSIONS: The results also suggested the promising use of AAM (viscogel B8) and the new nanocomposite prepared by clay/PVP K-30 intercalation as a new matrix for sustained release and the feasibility of using these new nanocomposites as dissolution enhancer.

Sulphonamide and sulphonyl-hydrazone cyclic imide derivatives: Antinociceptive activity, molecular modeling and In Silico ADMET screening

In this paper, we describe the antinociceptive activity, molecular modeling and in silico ADMET screening of a series of sulphonyl-hydrazone and sulphonamide imidobenzene derivatives. Among these compounds, the sulphonyl-hydrazones 9 and 11 showed the most potent analgesic activity (ID50 = 5.1 and 6.8 μmol/kg, respectively). Interestingly, all derivatives evaluated in this study have a better analgesic profile than the control drugs, acetyl salicylic acid and acetaminophen. Derivative 9 was the most promising compound; with a level of activity that was 24 times higher than the control drugs. Our SAR study showed a relationship among the distribution of the frontier orbital HOMO coefficients, HOMO-LUMO energy gap of these molecules and their reactivity. The best analgesic compounds (including 6, 9, 10, 11 and 12) fulfilled the Lipinski “rule-of-five”, which is theoretically important for good drug absorption and permeation.

Identification of a Potential Lead Structure for Designing New Antimicrobials to Treat Infections Caused by Staphylococcus epidermidis-Resistant Strains

Bacterial infections are a significant cause of morbidity and mortality among critically ill patients. The increase of antibiotic resistance in bacteria from human microbiota—such as Staphylococcusepidermidis, an important nosocomial pathogen that affects immunocompromised patients or those with indwelling devices—increased the desire for new antibiotics. In this study we designed, synthesized, and determined the antimicrobial activity of 27 thieno[2,3-b]pyridines (1, 2, 2a–2m, 3, 3a–3m) derivatives against a drug-resistant clinical S. epidermidis strain. In addition, we performed a structure-activity relationship analysis using a molecular modeling approach, and discuss the drug absorption, distribution, metabolism, excretion, and toxicity profile and Lipinski’s “rule of five,” which are tools to assess the relationship between structures and drug-like properties of active compounds. Our results showed that compound 3b (5-(1H-tetrazol-5-yl)-4-(3`-methylphenylamino)thieno[2,3-b]pyridine) was as active as oxacillin and chloramphenicol but with lower theoretical toxicity risks and a better drug likeness and drug score potential than chloramphenicol. All molecular modeling and biological results reinforced the promising profile of 3b for further experimental investigation and development of new antibacterial drugs.

Therapeutic Nanosystems for Oral Administration of Insulin

The treatment of Diabetes Mellitus (DM), a chronic disease, is primarily based upon administration of insulin forms to patients. Conventional subcutaneous administration is associated with a large number of complications, therefore, several new strategies have been developed. Amongst these strategies, oral insulin administration is much less invasive and, therefore, well tolerated. In recent years, various nanoformulations were developed for the oral administration of insulin, allowing more effective stabilization of the active pharmaceutical ingredient and modified for better absorption along the gastrointestinal tract. The development of different oral insulin nanoformulations in academic research as well as in patents, including the development of nanoparticles, liposomes, nanoemulsions and the use of cyclodextrins deserves special attention. The future of oral insulin nanoformulations is dependent on strategies utilizing simple technologies that stabilize the raw material, including inclusion within cyclodextrins or inclusion in low weight molecular mass polymers/ oligomers. All of the theories developed here provide a solid foundation upon which to develop new methods for the production of pharmaceutical peptide formulations. In addition, the effective search for existing nanometric formulations of insulin could provide economically viable therapeutic options that can consequently be produced on an industrial scale.

Platelets: Still a Therapeutical Target for Haemostatic Disorders

Platelets are cytoplasmatic fragments from bone marrow megakaryocytes present in blood. In this work, we review the basis of platelet mechanisms, their participation in syndromes and in arterial thrombosis, and their potential as a target for designing new antithrombotic agents. The option of new biotechnological sources is also explored.

Searching for new antileishmanial lead drug candidates: Synthesis, biological and theoretical evaluations of promising thieno(2,3-b)pyridine derivatives

Cutaneous leishmaniasis is a parasitic disease associated with high morbidity and mortality rates. This work reports the synthesis, biological and theoretical evaluations of a new antileishmanial series of 5(4,5-dihydro-1H-imidazol-2-yl)-4-(arylamino)thieno[2,3-b]pyridine derivatives - 3 (H), 3a (m-CH3), 3b (mOCH3), 3c (m-NO2), 3d (m-F), 3e (m-Br), 3f (p-CH3), 3g (p-OCH3), 3h (p-NO2), 3i (p-F), 3j (p-Br). Interestingly 3f and 3g showed a better profile against Leishmania amazonensis (EC50=29.49 and 32.23 μM, respectively) than glucantime, the current drug on the market (EC50=163.7 μM). The theoretical analysis pointed a correlation among the antileishmanial profile and the conformational and