In Silico Antiprotozoal Evaluation of 1,4-Naphthoquinone Derivatives against Chagas and Leishmaniasis Diseases Using QSAR, Molecular Docking, and ADME Approaches.

Chagas and leishmaniasis are two neglected diseases considered as public health problems worldwide, for which there is no effective, low-cost, and low-toxicity treatment for the host. Naphthoquinones are ligands with redox properties involved in oxidative biological processes with a wide variety of activities, including antiparasitic. In this work, in silico methods of quantitative structure-activity relationship (QSAR), molecular docking, and calculation of ADME (absorption, distribution, metabolism, and excretion) properties were used to evaluate naphthoquinone derivatives with unknown antiprotozoal activity. QSAR models were developed for predicting antiparasitic activity against Trypanosoma cruzi, Leishmania amazonensis, and Leishmania infatum, as well as the QSAR model for toxicity activity. Most of the evaluated ligands presented high antiparasitic activity. According to the docking results, the family of triazole derivatives presented the best affinity with the different macromolecular targets. The ADME results showed that most of the evaluated compounds present adequate conditions to be administered orally. Naphthoquinone derivatives show good biological activity results, depending on the substituents attached to the quinone ring, and perhaps the potential to be converted into drugs or starting molecules.

Antiprotozoal QSAR modelling for trypanosomiasis (Chagas disease) based on thiosemicarbazone and thiazole derivatives.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains a neglected endemic infection that affects around 8 million people worldwide and causes 12,000 premature deaths per year. Traditional chemotherapy is limited to the nitro-antiparasitic drugs Benznidazole and Nifurtimox, which present serious side effects and low long-term efficacy. Several research efforts have been made over the last decade to find new chemical structures with better effectiveness and tolerance than standard anti-Chagas drugs. Among these, new sets of thiosemicarbazone and thiazole derivatives have exhibited potent in vitro activity against T. cruzi, especially for its extracellular forms (epimastigote and trypomastigote). In this work, we have developed three antiprotozoal quantitative structure-relationship (QSAR) models for Chagas disease based on the in vitro activity data reported as IC50 (µM) and CC50 (µM) over the last decade, particularly by Lima-Leite's group in Brazil. The models were developed using the replacement method (RM), a technique based on Multivariable Linear Regression (MLR), and external and internal validation methodologies, like the use of a test set, Leave-one-Out (LOO) cross-validation and Y-Randomization. Two of these QSAR models were developed for trypomastigotes form of the parasite Trypanosoma cruzi, one based on IC50 and the other on CC50 data; while the third QSAR model was developed for its epimastigotes form based on CC50 activity. Our models presented sound statistical parameters that endorses their prediction capability. Such capability was tested for a set of 13 hitherto-unknown structurally related aromatic cyclohexanone derivatives.

Crystal structure, spectroscopic characterization and Hirshfeld surface analysis of aqua-dichlorido-{N-[(pyridin-2-yl)methyl-idene]aniline}copper(II) monohydrate.

The reaction of N-phenyl-1-(pyridin-2-yl)methanimine with copper chloride dihydrate produced the title neutral complex, [CuCl2(C12H10N2)(H2O)]·H2O. The CuII ion is five-coordinated in a distorted square-pyramidal geometry, in which the two N atoms of the bidentate Schiff base, as well as one chloro and a water mol-ecule, form the irregular base of the pyramidal structure. Meanwhile, the apical chloride ligand inter-acts through a strong hydrogen bond with a water mol-ecule of crystallization. In the crystal, mol-ecules are arranged in pairs, forming a stacking of symmetrical cyclic dimers that inter-act in turn through strong hydrogen bonds between the chloride ligands and both the coordinated and the crystallization water mol-ecules. The mol-ecular and electronic structures of the complex were also studied in detail using EPR (continuous and pulsed), FT-IR and Raman spectroscopy, as well as magnetization measurements. Likewise, Hirshfeld surface analysis was used to investigate the inter-molecular inter-actions in the crystal packing.

Novel Guanidine Compound against Multidrug-Resistant Cystic Fibrosis-Associated Bacterial Species.

Chronic pulmonary infection is a hallmark of lung disease in cystic fibrosis (CF). Infections dominated by non-fermentative Gram-negative bacilli are particularly difficult to treat and highlight an urgent need for the development of new class of agents to combat these infections. In this work, a small library comprising thiourea and guanidine derivatives with low molecular weight was designed; these derivatives were studied as antimicrobial agents against Gram-positive, Gram-negative, and a panel of drug-resistant clinical isolates recovered from patients with CF. One novel compound, a guanidine derivative bearing adamantane-1-carbonyl and 2-bromo-4,6-difluouro-phenyl substituents (H-BDF), showed potent bactericidal activity against the strains tested, at levels generally higher than those exhibited by tobramycin, ceftazimide and meropenem. The role that different substituents exert in the antimicrobial activity has been determined, highlighting the importance of the halo-phenyl group in the guanidine moiety. The new compound displays low levels of cytotoxicity against THP-1 and A549 cells with a selective index (SI) > 8 (patent application PCT/IB2017/054870, August 2017). Taken together, our results indicate that H-BDF can be considered as a promising antimicrobial agent.