In vitro anti-Leishmania activity and molecular docking of spiro-acridine compounds as potential multitarget agents against Leishmania infantum.

Leishmaniasis is an infectious disease with several limitations regarding treatment schemes. This work reports the anti-Leishmania activity of spiroacridine compounds against the promastigote (IC50 = 1.1 to 6.0 µg / mL) and amastigote forms of the best compounds (EC50 = 4.9 and 0.9 µg / mL) inLeishmania (L.) infantumand proposes an in-silico study with possible selective therapeutic targets for L. infantum. The substituted dimethyl-amine compound (AMTAC 11) showed the best leishmanicidal activity in vitro, and was found to interact with TryRandLdTopoI. comparisons with standard inhibitors were performed, and its main interactions were elucidated. Based on the biological assessment and the structure-activity relationship study, the spiroacridine compounds appear to be promisinganti-leishmaniachemotherapeutic agents to be explored.

Pharmacophore Modeling, Synthesis, Scaffold Hopping and Biological ß- Hematin Inhibition Interaction Studies for Anti-malaria Compounds.

Backgound: Exploring potent compounds is critical to generating multi-target drug discovery. Hematin crystallization is an important mechanism of malaria. METHODS: A series of chloroquine analogues were designed using a repositioning approach to develop new anticancer compounds. Protein-ligand interaction fingerprints and ADMET descriptors were used to assess docking performance in virtual screenings to design chloroquine hybrid ß-hematin inhibitors. A PLS algorithm was applied to correlate the molecular descriptors to IC50 values. The modeling presented excellent predictive power with correlation coefficients for calibration and cross-validation of r2 = 0.93 and q2 = 0.72. Using the model, a series of 4-aminoquinlin hybrids were synthesized and evaluated for their biological activity as an external test series. These compounds were evaluated for cytotoxic cell lines and ß-hematin inhibition. RESULTS: The target compounds exhibited high ß-hematin inhibition activity and were 3-9 times more active than the positive control. Furthermore, all the compounds exhibited moderate to high cytotoxic activity. The most potent compound in the dataset was docked with hemoglobin and its pharmacophore features were generated. These features were used as input to the Pharmit server for screening of six databases. CONCLUSION: The compound with the best score from ChEMBL was 2016904, previously reported as a VEGFR-2 inhibitor. The 11 compounds selected presented the best Gold scores with drug-like properties and can be used for drug development.

Docking of Natural Products against Neurodegenerative Diseases: General Concepts.

BACKGROUND: Since antiquity, humanity has used medicinal plant preparations to cure its ills, and, as research has progressed, new technologies have enabled more investigations on natural compounds which originate from plants, fungi, and marine species. The health benefits that these natural products provide have become a motive for treatment studies of various diseases. OBJECTIVE: Among them, the neurodegenerative diseases like Alzheimer's and Parkinson's, a major age-related neurodegenerative disorder. Studies with natural products for neurodegenerative diseases (particularly through molecular docking) search for, and then focus on those ligands which offer effective inhibition of the enzymes monoamine oxidase and acetylcholinesterase. METHOD: This review introduces the main concepts involved in docking studies with natural products: and also in our group, which has conducted a docking study of natural products isolated from Tetrapterys mucronata for inhibition of acetylcholinesterase. RESULTS: We observed that compounds 4 and 5 formed more interactions than the theoretical ligand, but that ligands with greater activity also interacted with residues HIS 381 and GLN 527. CONCLUSION: We have reported on our docking study performed with AChE and alkaloids isolated from the plant Tetrapterys mucronata. Our docking results corroborate the experiments conducted, and emphasize the positive contribution that these theoretical studies involving natural products bring to the fight against neurodegenerative diseases.

Anthocyanins: Multi-Target Agents for Prevention and Therapy of Chronic Diseases.

Anthocyanins, a flavonoid class of polyphenols, are water soluble dark colored natural pigments found in fruits and vegetables. Owing to their wide distribution in plant materials, dietary consumption of anthocyanins is high compared to other flavonoids. Anthocyanins, due to their multifaceted medicinal properties are the active components in many herbal folk medicines. As in vitro and in vivo results, animal models, and clinical trials in various cell lines suggest, anthocyanins possess antioxidant, antidiabetic, antihyperlipidemic, anti-inflammatory, anticarcinogenic, antiulcer, and preventive activities against cardiovascular diseases. Additionally, anthocyanins exhibit chemotherapeutic, cardioprotective, hepatoprotective, and neuroprotective activities. In the diet, anthocyanins are absorbed in the stomach and intestinal cells and rapidly detected in the plasma. These promising properties of anthocyanins may well provide health benefits against chronic diseases.

In silico and In vivo Toxicological Evaluation of Cissampelos Sympodialis Secondary Metabolites in Rattus Norvegicus.

Cissampelos sympodialis is a plant in northeastern Brazil used by the populace for treating respiratory diseases. Several studies have shown that ethanol leaf extracts have immunomodulatory and anti-inflammatory activities. Infusions are widely used, popular, and an ancient technique in traditional medicine, using hot water alone as the means of extraction. This study aimed to investigate acute toxicological potential of leaf infusions of Cissampelos sympodialis, when applied orally at a dose of 2000mg/kg to Rattus norvegicus, combined with an in silico study of 117 alkaloids present in the Cissampelos genus; five (5) of which were determined to have high toxicity (21, 8, 93, 32 and 88), and five (5) having both low toxicity (57, 77, 28, 25 and 67) and low liver metabolism. The in vivo toxicological evaluation showed that male water consumption decreased, and the feed intake decreased in both sexes. Yet, the figures as to change in weight gain of the animals were not statistically sufficient. As for the biochemical parameters, there was an increase in urea, and decreases in uric acid and AST in males. In females, there was a decrease in albumin and globulin which consequently leads to a total protein decrease. Despite biochemical changes suggestive of kidney damage, the histological sections revealed no kidney or liver changes. The results therefore indicate that despite presenting alkaloids which may be toxic, the genus Cissampelos, or leaf infusions of Cissampelos sympodialis, when applied orally at a dose of 2000mg/kg present low toxicity.

Docking Studies for Multi-Target Drugs.

The most basic principle of drug action is found in the lock and key model, where the highest possible affinity for a target that also avoids side effects is desired. For many years this was understood as being "one drug, for one target, for one disease", however researchers began to observe that certain diseases are best treated with multi-target drugs. In recent years, studies have sought out polypharmacological compounds acting on multiple targets against complex (multifactorial) diseases, such as cancer, neurodegenerative disease, and certain infections. One of the computational tools used in research for multifunctional drugs is Molecular Docking. Through this methodology of Computer-Aided Drug Design, we observe complexes formed between ligands and interesting targets (often many), for a particular disease. This review reports on docking studies as used in investigations of new multi-target compounds; it also shows the various ways that such studies are used in the search for multifunctional compounds.

Antileishmanial activity of new thiophene-indole hybrids: Design, synthesis, biological and cytotoxic evaluation, and chemometric studies.

In the present work, thirty-two hybrid compounds containing cycloalka[b]thiophene and indole moieties (TN5, TN5 1-7, TN6, TN6 1-7, TN7, TN7 1-7, TN8, TN8 1-7) were designed, synthesized and evaluated for their cytotoxic and antileishmanial activity against Leishmania amazonensis promastigotes. More than half of the compounds (18 compounds) exhibited significant antileishmanial activity (IC50 lower than 10.0µg/L), showing better performance than the reference drugs (tri- and penta-valent antimonials). The most active compounds were TN8-7, TN6-1 and TN7 with respective IC50 values of 2.1, 2.3 and 3.2µg/mL. Demonstrating that all of the compounds were less toxic than the reference drugs, even at the highest evaluated concentration (400µg/mL), no compound tested presented human erythrocyte cytotoxicity. Compound TN8-7's effectiveness against a trivalent antimony-resistant culture was demonstrated. It was observed that TN8-7's antileishmanial activity is associated with DNA fragmentation of L. amazonensis promastigotes. Chemometric studies (CPCA, PCA, and PLS) highlight intrinsic solubility/lipophilicity, and compound size and shape as closely related to activity. Our results suggest that hybrid cycloalka[b]thiophene-indole derivatives may be considered as lead compounds for further development of new drugs for the treatment of leishmaniasis.

Multi-Target Drugs for Neglected Diseases.

BACKGROUND: Diseases perceived as neglected tropical infections are generally caused by parasites which reach poor, underserved populations (primarily infrastructure), cause serious damage to health, and many deaths. AIDS and tuberculosis, (although not classified as neglected by WHO), are discriminated against infections which cause great social damage. The drugs currently used to treat these diseases do not have the desired effectiveness, enable the emergence of resistant strains, and in most cases are difficult to obtain. Few pharmaceutical companies are investing in new drug research for neglected diseases, for lack of financial return. This review reports the major neglected diseases, AIDS, tuberculosis, their targets, and research on multi-target drugs. METHODS: The studies for new drugs against these infections involve in silico methods, synthesis, structural determinations, analytical analysis and other experimental assays. RESULTS: A new single compound, forecasting possible pharmacodynamic and pharmacokinetic interactions becomes a simpler process; it is also believed that these drugs are safer and more efficient, since they act with synergism on different targets. It occurs but the emergence of new resistant strains and side effects. CONCLUSION: Multi-target drugs represent a new alternative to find new lead compounds. A ligand that targets two or more receivers may be seen as a potential drug, combating infection by different routes.

Computational and Investigative Study of Flavonoids Active Against Typanosoma cruzi and Leishmania spp.

Flavonoid compounds active against Trypanosoma cruzi and Leishmania species were submitted to several methodologies in silico: docking with the enzymes cruzain and trypanothione reductase (from T. cruzi), and N-myristoyltransferase, dihydroorotate dehydrogenase, and trypanothiona reductase (from Leishmania spp). Molecular maps of the complexes and the ligands were calculated. In order to compare and evaluate the antioxidant activity of the flavonoids with their antiprotozoal activity, quantum parameters were calculated. Considering the energies, interactions, and hydrophobic surfaces calculated, the flavonoids chrysin dimethyl ether against T. cruzi, and ladanein against Leishmania sp. presented the best results. The antioxidant activity did not show any correlation with anti-parasitic activity; only chrysin and its dimethyl ether showed favorable anti-parasitic results. This study hopes to contribute to existing research on these natural products against these tropical parasites.