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This article reports a novel virtual screening algorithm seeking the rational identification of novel lead anticoagulants. Seven 5-(3-methyl-1-aryl-1H-pyrazol-4-yl)-1H-tetrazoles and seven novel 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-3-methyl-1H-pyrazoles were obtained in three steps starting from arylhydrazine hydrochlorides as raw materials in good yields: 50-72% and 50-85%, respectively. All compounds were submitted to an in silico target-base pipeline named integrated multiplex analysis virtual screening (IMA-VS), which comprises the evaluation of their (i) fitting physicochemical properties to the chemical environment of the target enzyme; (ii) active-site homing electrostatic potential to the target enzyme; (iii) structural fitting to the target active site through molecular docking; and (iv) overall absorption, distribution, metabolism, excretion and toxicity (ADMET) profile. After the virtual selection of potential anticoagulant hits, all molecules were synthesized and candidates were evaluated in vitro for their anticoagulant and hemolytic profile. The most promising candidate pointed out by IMA-VS was compound 1-(3',4'-dichlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-3-methyl-1H-pyrazole that shown to display factor Xa (FXa)-specific inhibitory activity in vitro, acting as an uncompetitive inhibitor with an inhibition constant (Ki) = 61.16 ± 12.96 µM, in addition to the lowest hemolytic activity of the series. Further experiments revealed the antithrombotic activity of this compound in an in vivo model of arterial thrombosis induced by FeCl 3 .

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Essential oils from Amazonian species are gaining increasing interest worldwide due to their medicinal and cosmetic applications; however, the relation among the chemical constituents and their biological properties are not well explored. Therefore, the present research aims to obtain an understanding of the bioactivity of chemical compounds in the essential oils of plants from the Annonaceae family (Bocageopsis pleiosperma, Onychopetalum amazonicum, Unonopsis duckei, U. floribunda, U. rufescens, U. stipitata, U. guatterioides, Duguetia flagelaris and Xylopia benthamii). By means of gas chromatography coupled to mass spectrometry, in vitro cytotoxic and anti-lipase assays, principal component analysis and molecular docking, it was possible to establish the main compounds that may be responsible for the cytotoxic effect of O. amazonicum and B. pleiosperma. Moreover, the anti-lipase potential of D. flagerallaris was also established, as well as its composition related to the activity. Thus, by the employed strategy, allo-aromadendrene, cryptomerione, δ-cadinene and β-bisabolene were suggested as plausible cytotoxic agents against cancer cell lines, and dehydroaromadendrene, spathulenol and elemol, against lipase. The present study provides significant information on the chemical profile and bioactivity studies of Amazon Annonaceae aromatic plants.

Trichoderma is recognized as a prolific producer of nonribosomal peptides (NRPs) known as peptaibols, which have remarkable biological properties, such as antimicrobial and anticancer activities, as well as the ability to promote systemic resistance in plants against pathogens. In this study, the sequencing of 11-, 14- and 15-res peptaibols produced by a marine strain of Trichoderma isolated from the ascidian Botrylloides giganteus was performed via liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/MS). Identification, based on multilocus phylogeny, revealed that our isolate belongs to the species T. endophyticum, which has never been reported in marine environments. Through genome sequencing and genome mining, 53 biosynthetic gene clusters (BGCs) were identified as being related to bioactive natural products, including two NRP-synthetases: one responsible for the biosynthesis of 11- and 14-res peptaibols, and another for the biosynthesis of 15-res. Substrate prediction, based on phylogeny of the adenylation domains in combination with molecular networking, permitted extensive annotation of the mass spectra related to two new series of 15-res peptaibols, which are referred to herein as “endophytins”. The analyses of synteny revealed that the origin of the 15-module peptaibol synthetase is related to 18, 19 and 20-module peptaibol synthetases, and suggests that the loss of modules may be a mechanism used by Trichoderma species for peptaibol diversification. This study demonstrates the importance of combining genome mining techniques, mass spectrometry analysis and molecular networks for the discovery of new natural products.

: Serious fungal infections are increasing worldwide and became a great concern in the medical field since antifungal drugs are restricted to a few drug classes. This work aims to evaluate the antifungal activity of a series of 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (1a-g) and to establish a structure-activity relationship (SAR). Synthesis of these compounds occurred in a single step followed by cyclization in good to excellent yields: 73-94%. The chemical structures were confirmed by melting point, IR, 1H-NMR, 13C-NMR, and HRMS. These seven compounds were submitted to the disk diffusion test against Candida spp. and the active compound was evaluated by means of the broth microdilution method to determine the minimum inhibitory concentration (MIC). In addition, the stereo-electronic descriptors were evaluated and pharmacokinetic and toxicological proprieties were calculated to predict the potential of these compounds as a drug. All compounds presented good theoretical physicochemical parameters and one of them showed reasonably good antifungal activity.