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N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The design, synthesis, in vitro evaluation, and conformational study of nitrosopyrimidine derivatives acting as antifungal agents are reported. Different compounds structurally related with 4,6-bis(alkyl or arylamino)-5-nitrosopyrimidines were evaluated. Some of these nitrosopyrimidines have displayed a significant antifungal activity against human pathogenic strains. In this paper, we report a new group of nitrosopyrimidines acting as antifungal agents. Among them, compounds 2a, 2b and 15, the latter obtained from a molecular modeling study, exhibited antifungal activity against Candida albicans, Candida tropicalis and Cryptococcus neoformans. We have performed a conformational and electronic analysis on these compounds by using quantum mechanics calculations in conjunction with Molecular Electrostatic Potentials (MEP) obtained from B3LYP/6-31G(d) calculations. Our experimental and theoretical results have led us to identify a topographical template which may provide a guide for the design of new nitrosopyrimidines with antifungal effects., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The synthesis, in vitro evaluation, and conformational study of a new series of small-size peptides acting as antifungal agents are reported. In a first step of our study we performed a conformational analysis using Molecular Mechanics calculations. The electronic study was carried out using Molecular electrostatic potentials (MEPs) obtained from RHF/6-31G calculations. On the basis of the theoretical predictions three small-size peptides, RQWKKWWQWRR-NH(2), RQIRRWWQWRR-NH(2), and RQIRRWWQW-NH(2) were synthesized and tested. These peptides displayed a significant antifungal activity against human pathogenic strains including Candida albicans and Cryptococcus neoformans. Our experimental and theoretical results allow the identification of a topographical template which can serve as a guide for the design of new compounds with antifungal properties for potential therapeutic applications against these pathogenic fungi., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Three series of 1-substituted-7-chloro-6-hydroxy-tetrahydroisoquinolines (1-butyl-, 1-phenyl- and 1-benzyl derivatives) were prepared to explore the influence of each of these groups at the 1-position on the affinity for dopamine receptors. All the compounds displayed affinity for D(1)-like and/or D(2)-like dopamine receptors in striatal membranes, and were unable to inhibit [(3)H]-dopamine uptake in striatal synaptosomes. Different structure requirements have been observed for adequate D(1) or D(2) affinities. This paper details the synthesis, structural elucidation, dopaminergic binding assays, structure-activity relationships (SAR) of these three series of isoquinolines. Moreover, 1-butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline (1e) with the highest affinity towards D(2)-like receptors (K(i) value of 66nM) and the highest selectivity (49-fold D(2) vs D(1)) by in vitro binding experiments was then evaluated in behavioral assays (spontaneous activity and forced swimming test) in mice. Compound 1e increased locomotor activity in a large dose range (0.04-25mg/kg). Furthermore, this lead compound produced reduction in immobility time in the forced swimming test at a dose (0.01mg/kg) that did not modify locomotor activity. The haloperidol (0.03mg/kg), a D(2) receptor preferred antagonist, blocked the antidepressant-like effect of compound 1e.

The synthesis, in vitro evaluation and conformational study of His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH(2) and analogues acting as antifungal agents are reported. Among them, His-Phe-Lys-Trp-Gly-Arg-Phe-Val-NH(2) exhibited a moderate but significant antifungal activity against Cryptococcus neoformans, Candida albicans and Candida tropicalis. A theoretical study allows us to propose a biologically relevant conformation for these octapeptides acting as antifungal agents. In addition, these theoretical calculations allow us to determine the minimal structural requirements to produce the antifungal response and can provide a guide for the design of compounds with this biological activity.

The cytotoxic effects of four alkaloids, berberine, canadine, anonaine, and antioquine were evaluated using three different cell cultures, a primary culture (rat hepatocytes) and two cell lines (HepG2 and HeLa). Our results indicate that berberine, anonaine, and antioquine possess a significant the cytotoxic effect. In contrast, canadine does not possess cytotoxic effect at concentrations tested here. A molecular modeling study indicates that the quaternary nitrogen, the aromatic polycyclic and planar structure of berberine could be the pharmacophoric patron to produce the cytotoxic effect. In parallel our results demonstrated that canadine possess a significant antioxidant activity. Stereoelectronic aspects of this alkaloid were found to be closely related to those displayed by alpha-tocopherol and its water-soluble analogue trolox. The antioxidant activities of canadine, combined with its low-toxic effect, indicated that the potential of this alkaloid as a novel class of antioxidant agent is very interesting and deserves further research.

Brain dopaminergic system has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression, and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to synthesize N-[2-(4,5-dihydroxyphenyl)-methyl-ethyl]-4,5-dihydroxy-2-aminoindan hydrobromide (3), planned to be a dopamine ligand, and to evaluate its dopaminergic action profile. This compound was assayed as a diastereoisomeric mixture in two experimental models: stereotyped behavior (gnaw) and renal urinary response, after central administration. The pharmacological results showed that compound 3 significantly blocked the apomorphine-induced stereotypy and dopamine-induced diuresis and natriuresis in rats. Thus, compound 3 demonstrated an inhibitory effect on dopaminergic-induced behavior and renal action. N-[2-(-Methyl-ethyl)]-4,5-dihydroxy-2-aminoindan hydrobromide (4) was previously reported as an inotropic agent, and in the present work it was also re-evaluated as a diastereoisomeric mixture for its possible central action on the behavior parameters such as stereotypy and dopamine-induced diuresis and natriuresis in rats. Our results indicate that compound 4 produces an agonistic response, possibly through dopaminergic mechanisms. To better understand the experimental results we performed molecular dynamics simulations of two complexes: compound 3/D(2)DAR (dopamine receptor) and compound 4/D(2)DAR. The differential binding mode obtained for these complexes could explain the antagonist and agonist activity obtained for compounds 3 and 4, respectively.

Diverse N-substituted anilines bearing hetaryl fragments were easily prepared from corresponding aldimines derived from commercially available aromatic aldehydes and anilines. 2-Furyl substituted anilines showed very good antifungal activities against dermatophytes, particularly against Trichophyton rubrum (MIC=3.12-6.25microg/mL). In addition, all active compounds, 45-47, 73, and 74, were tested for cytotoxic activities against breast (MCF-7), lung (H-460), and central nervous system (SF-268) human cancer cell lines with the NCI-anticancer-drug screen. The activity of amines described in this paper, along with the low toxicity of most of them, shows promise for the future development of non-toxic new antimycotic agents.

We describe herein the isolation and semisynthesis of four acetogenin derivatives (1-4) as well as their ability to inhibit the mitochondrial respiratory chain and several tumor cell lines. In addition, four nanoseconds (ns) of MD simulation of compound 4, in a fully hydrated POPC bilayer, is reported.

An efficient microwave-assisted synthesis of new (Z)-5-arylidenerhodanines under solvent-free conditions is described and their in vitro antifungal activity was evaluated following the CLSI (formerly NCCLS) guidelines against a panel of both standardized and clinical opportunistic pathogenic fungi. An analysis of the structure-activity relationship (SAR) along with computational studies showed that the most active compounds (F- and CF(3)-substituted rhodanines) possess high logP values and low polarizability. Mechanism-based assays suggest that active compounds neither would bind to ergosterol nor would produce a damage to the fungal membrane.

The synthesis, in vitro evaluation, and conformational study of His-Phe-Arg-Trp-NH2 and related derivatives acting as antifungal agents are reported. Among them, His-Phe-Arg-Trp-NH2 and His-Tyr-Arg-Trp-NH2 exhibited antifungal activity against Cryptococcus neoformans. Antifungal activity of these compounds appears to be closely related to the alpha-MSH effect. A conformational and electronic study allows us to propose a biologically relevant conformation for these tetrapeptides acting as antifungal agents. In addition, these theoretical calculations permit us to determine the minimal structural requirements to produce the antifungal response and may provide a guide for the design of compounds with this biological activity.

The synthesis, in vitro evaluation, and structure-activity relationship studies of homoallylamines and related derivatives acting as antifungal agents are reported. Among them, compounds N-(4-bromophenyl)-N-(2-furylmethyl)amine and N-(4-chlorophenyl)-N-(2-furylmethyl)amine reported here exhibited remarkable antifungal activity against dermatophytes. Theoretical calculations allow us to determine the minimal structural requirements to produce the antifungal response and can provide a guide for the design of compounds with these properties.

The synthesis, in vitro antifungal evaluation and SAR studies of 101 compounds of the 4-aryl-, 4-alkyl-, 4-pyridyl or -quinolinyl-4-N-arylamino-1-butenes series and related compounds, are reported here. Active structures showed to inhibit (1,3)-beta-D-glucan and mainly chitin synthases, enzymes that catalyze the synthesis of the major fungal cell wall polymers.

Here we report the synthesis, in vitro antifungal evaluation and SAR study of 41 chalcones and analogues. In addition, all active structures were tested for their capacity of inhibiting Saccharomyces cerevisiae beta(1,3)-glucan synthase and chitin synthase, enzymes that catalyze the synthesis of the major polymers of the fungal cell wall.

As part of our project devoted to the search for antifungal agents, which act via a selective mode of action, we synthesized a series of new 4-aryl- or 4-alkyl-N-arylamine-1-butenes and transformed some of them into 2-substituted 4-methyl-tetrahydroquinolines and quinolines by using a novel three-step synthesis. Results obtained in agar dilution assays have shown that 4-aryl homoallylamines not possessing halogen in their structures, tetrahydroquinolines and quinolines, display a range of antifungal properties in particular against Epidermophyton floccosum and Microsporum canis. Regarding the mode of action, all active compounds showed in vitro inhibitory activities against beta(1-3) glucan-synthase and mainly against chitin-synthase. These enzymes catalyze the synthesis of beta(1-3) glucan and chitin, respectively, major polymers of the fungal cell wall. Since fungal but not mammalian cells are encased in a cell wall, its inhibition may represent a useful mode of action for these antifungal compounds.