Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi.

Chagas disease (CD) still represents a serious public health problem in Latin America, even after more than 100 years of its discovery. Clinical treatments (nifurtimox and benznidazole) are considered inadequate, especially because of undesirable side effects and low efficacy in the chronic stages of the disease, highlighting the urgency for discovering new effective and safe drugs. A small library of compounds (1a-i and 2a-j) was designed based on the structural optimization of a Hit compound derived from 1,4-naphthoquinones (C2) previously identified. The biological activity, structure-activity relationship (SAR), and the in silico physicochemical profiles of the naphthoquinone derivatives were analyzed. Most modifications resulted in increased trypanocidal activity but some substitutions also increased toxicity. The data reinforce the importance of the chlorine atom in the thiophenol benzene ring for trypanocidal activity, highlighting 1g, which exhibit a drug-likeness profile, as a promising compound against Trypanosoma cruzi. SAR analysis also revealed 1g as cliff generator in the structure-activity similarity map (SAS maps). However, compounds C2 and 1g were unable to reduce parasite load, and did not prevent mouse mortality in T. cruzi acute infection. Phenotypic screening and computational analysis have provided relevant information to advance the optimization and design of new 1,4-naphthoquinone derivatives with a better pharmacological profile.

Antibacterial naphthoquinone derivatives targeting resistant strain Gram-negative bacteria in biofilms.

The aims of this study were the planning, synthesis and in vitro evaluation of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against Gram-negative and Gram-positive strains, searching for potential lead compounds against bacterial biofilm formation. A series of 12 new analogs of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones were synthesized by adding a thiol and different substituents to a ο-quinone methide using microwave irradiation. The compounds were tested against Gram-positive (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. simulans ATCC 27851, S. epidermidis ATCC 12228 and a hospital Methicillin-resistant S. aureus (MRSA) strain), as well as Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, P. aeruginosa ATCC 15442, Proteus mirabilis ATCC 15290, Serratia marcescens ATCC 14756, Klebsiella pneumoniae ATCC 4352 and Enterobacter cloacae ATCC 23355) strains, using the disk diffusion method. Ten compounds showed activity mainly against Gram-negative strains with a minimal inhibitory concentration (MIC = 4-64 µg/mL) within the Clinical and Laboratory Standards Institute (CLSI) levels. The biofilm inhibition data showed compounds, 9e, 9f, 9j and 9k, are anti-biofilm molecules when used in sub-MIC concentrations against P. aeruginosa ATCC 15442 strain. Compound (9j) inhibited biofilm formation up to 63.4% with a better profile than ciprofloxacin, which is not able to prevent biofilm formation effectively. The reduction of P. aeruginosa ATCC 15442 mature biofilms was also observed for 9e and 9k. The structure modification applied in the series resulted in 12 new naphthoquinones with antimicrobial activity against Gram-negative bacteria strains (E. coli ATCC 25922, P. aeruginosa ATCC 27853 and ATCC 15442). Four compounds decreased P. aeruginosa biofilm formation effectively.

Efficient Catalytic Oxidation of 3-Arylthio- and 3-Cyclohexylthio-lapachone Derivatives to New Sulfonyl Derivatives and Evaluation of Their Antibacterial Activities.

New sulfonyl-lapachones were efficiently obtained through the catalytic oxidation of arylthio- and cyclohexylthio-lapachone derivatives with hydrogen peroxide in the presence of a Mn(III) porphyrin complex. The antibacterial activities of the non-oxidized and oxidized lapachone derivatives against the Gram-negative bacteria Escherichia coli and the Gram-positive bacteria Staphylococcus aureus were evaluated after their incorporation into polyvinylpyrrolidone (PVP) micelles. The obtained results show that the PVP-formulations of the lapachones 4b-g and of the sulfonyl-lapachones 7e and 7g reduced the growth of S. aureus.

Synthesis and anti-Trypanosoma cruzi activity of new 3-phenylthio-nor-ß-lapachone derivatives.

We report herein a straightforward and efficient one-step reaction to prepare new nor-ß-lapachone derivatives tethered with phenylthio groups at position 3 of the furan ring. We have screened the compounds on bloodstream trypomastigotes of Trypanosoma cruzi, the causative agent of Chagas disease, aimed at finding a new prototype with high trypanocidal activity. The new compounds possess a broad range of activity (IC50/24h from 9.2 to 182.7 µM), higher than the original quinone (391.5 µM) and four of them higher than standard drug benznidazole (103.6 µM). The most active was compound 13b (9.2 µM), being 11 times active than benznidazole and the less toxic derivative to heart muscle cells.

Biological evaluation of hydroxynaphthoquinones as anti-malarials.

BACKGROUND: The hydroxynaphthoquinones have been extensively investigated over the past 50 years for their anti-malarial activity. One member of this class, atovaquone, is combined with proguanil in Malarone®, an important drug for the treatment and prevention of malaria. METHODS: Anti-malarial activity was assessed in vitro for a series of 3-alkyl-2-hydroxy-1,4-naphthoquinones (N1-N5) evaluating the parasitaemia after 48 hours of incubation. Potential cytotoxicity in HEK293T cells was assessed using the MTT assay. Changes in mitochondrial membrane potential of Plasmodium were measured using the fluorescent dye Mitrotracker Red CMXROS. RESULTS: Four compounds demonstrated IC50s in the mid-micromolar range, and the most active compound, N3, had an IC50 of 443 nM. N3 disrupted mitochondrial membrane potential, and after 1 hour presented an IC50ΔΨmit of 16 µM. In an in vitro cytotoxicity assay using HEK 293T cells N3 demonstrated no cytotoxicity at concentrations up to 16 µM. CONCLUSIONS: N3 was a potent inhibitor of mitochondrial electron transport, had nanomolar activity against cultured Plasmodium falciparum and showed minimal cytotoxicity. N3 may serve as a starting point for the design of new hydroxynaphthoquinone anti-malarials.

Synthesis of new 9-hydroxy-α- and 7-hydroxy-ß-pyran naphthoquinones and cytotoxicity against cancer cell lines.

A synthetic method to obtain α- and ß-pyran naphthoquinones 10 and 11 with a hydroxyl substituent on the aromatic ring was developed. Two series of α- and ß-pyran naphthoquinones were obtained from the 8-hydroxy-lawsone, and their anticancer properties were evaluated against four tumor cell lines. In general, the new compounds displayed good activity, possibly indicating that these compounds have increased pro-oxidant capacity. The 9-hydroxy-α-lapachone and 7-hydroxy-ß-lapachone analogues of the natural products α-lapachone and ß-lapachone were successfully produced by this methodology.

Strategies for the Synthesis of Mono- and Bis-Thionaphthoquinones.

The subclass of compounds that have the nucleus 1, 4-naphthoquinone is the most diverse class of quinones, which have a large number of substances and have useful applications ranging from medicinal chemistry to application in materials with special properties. The introduction of one or two substituents with the sulfur heteroatom in the naphthoquinone nucleus generates products containing alkyl and aryl groups that amplify certain biological properties against bacteria, viruses, and fungi. There are several methods of preparing these compounds, mainly from low molecular weight naphthoquinones with two electrophilic sites capable of reacting with sulfides generating diversity and new classes of compounds, including new sulfur heterocycles and sulfur heterocycles fused with naphthoquinones. These compounds have been shown to be bioactive against several biological targets. This review will describe the methods of their synthesis and, when applicable, their biological activities.

Juglone: A Versatile Natural Platform for Obtaining New Bioactive Compounds.

Juglone is a metabolite produced by several species of plants, in particular Juglans nigra. Additionally, juglone is a 1,4-naphthoquinone that has several biological actions. Antimicrobial, antifungal, sedative, oxidizing, antihypertensive, and especially anti-proliferative actions have been described for juglone. This justifies that 1,4-naphthoquinone is a privileged structure for Medicinal Chemistry, and it is useful for the development of new prototypes with varied actions. In this work, we make a profound review of juglone synthesis methodology, the biological actions of juglone, and mainly the synthesis and pharmacological actions of juglone derivatives. We hope that the potent biological actions described for these derivatives in this review will stimulate the continuous design, synthesis, and pharmacological evaluation of new juglone derivatives.

Advances in drug discovery to assess cholinergic neurotransmission: a systematic review.

Neurotransmission is essential to physiological processes of cellular communication. The search for new molecules that may influence neurotransmission systems is an open field with possible impact on several pathophysiological conditions or diseases: Alzheimer's disease, Parkinsonism and myasthenia gravis, etc. The present review describes the most important aspects of cholinergic neurotransmission, as well as natural and synthetic compounds that, as clinical or experimental drugs, are able to influence this transmission. The pharmacological effects of substances that bind to muscarinic or nicotinic cholinergic receptors, along with their corresponding affinities will also be presented.

Selective and Sensitive Pull Down of Amyloid Fibrils Produced in Vitro and in Vivo by the Use of Pentameric-Thiophene-Coupled Resins.

Protein aggregation is a hallmark of several degenerative diseases, including Alzheimer's disease, Parkinson's disease and familial amyloidosis (Finnish type) (FAF). A method to isolate and detect amyloids is desired for the diagnosis of amyloid diseases. Here, we report the synthesis of pentameric thiophene amyloid ligand (p-FTAA) linked to agarose resin for selective purification of amyloid aggregates produced in vitro and in vivo. Using amyloid fibrils produced in vitro from α-synuclein, gelsolin, and Aß1-40 and gelsolin amyloid aggregates extracted from tissue homogenates of a mouse model of FAF, we observed that p-FTAA resin was able to pull down amyloid aggregates. The functionalized resin was also able to pull down oligomers produced in vitro from the A30P variant of α-synuclein. The methodology described here can be useful for the diagnosis of amyloidogenic disease and also can be used to purify amyloid fibrils from biological samples, rendering the fibrils available for more accurate structural and biochemical characterization.

Recent advances in the synthesis of new antimycobacterial agents based on the 1H-1,2,3-triazoles.

The 1H-1,2,3-triazoles have been studied for many years as an important class of heterocyclic compounds and still attracting considerable attention due to their several application such as, organocatalyst, ionic liquid and broad range of biological activities, including several neglected diseases as tuberculosis. This review emphasizes the recent advances of these triazoles and their perspective in the development of new bioactive chemical entities against tuberculosis.

Novel 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole derivatives: a patent review (2008 - 2011).

INTRODUCTION: The triazoles represent a class of five-membered heterocyclic compounds of great importance for the preparation of new drugs with diverse biological activities because they may present several structural variations with the same numbers of carbon and nitrogen atoms. Due to the success of various triazoles that entered the pharmaceutical market and are still being used in medicines, many companies and research groups have shown interest in developing new methods of synthesis and biological evaluation of potential uses for these compounds. In this review, the authors explored aspects of patents for the 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole families, including prototypes being considered in clinical studies between 2008 and 2011. AREAS COVERED: The triazoles have been studied for over a century as an important class of heterocyclic compounds and still attract considerable attention due to their broad range of biological activities. More recently, there has been considerable interest in the development of novel triazoles with anti-inflammatory, antiplatelet, antimicrobial, antimycobacterial, antitumoral and antiviral properties and activity against several neglected diseases. This review emphasizes recent perspective and advances in the therapeutically active 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole derivative patents between 2008 and 2011, covering the development of new chemical entities and new pharmaceuticals. Many studies have focused on these compounds as target structures and evaluated them in several biological targets. EXPERT OPINION: The preparation of 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole derivatives brings to light several issues. There is a need to find new, more efficient preparations for these triazoles that take into consideration current issues in green chemistry, energy saving and sustainability. New diseases are discovered and new viruses and bacteria continue to challenge mankind, so it is imperative to find new prototypes for these new diseases. Of great urgency is finding prototypes against bacteria that continue to increase resistance and for neglected diseases that affect a large part of humanity, especially the poor and vulnerable.

Addition of thiols to o-quinone methide: new 2-hydroxy-3-phenylsulfanylmethyl[1,4]naphthoquinones and their activity against the human malaria parasite Plasmodium falciparum (3D7).

A series of 36 new phenylsulfanylmethyl[1,4]naphthoquinones (7-42) were synthesized by a three-component reaction that involves lawsone, the appropriate aldehyde and thiols with variable substitution patterns. These reactions involve the in situ generation of o-quinone methides (o-QM) via Knoevenagel condensation and 1,4-nucleophilic addition under conventional heating or microwave irradiation. The new naphthoquinones obtained by this methodology were shown to have moderate to good in vitro antimalarial activity against Plasmodium falciparum (3D7).

Synthesis of 1,2,3-triazole glycoconjugates as inhibitors of α-glucosidases.

Ten new 1,2,3-triazole glycoconjugates were synthesized from d-glucose and evaluated in in vitro assays for their ability to inhibit the enzyme α-glucosidase. Most of the compounds had low activity or were inactive when compared with acarbose. However, the derivative 1,2-O-isopropylidene-3-phenyl-5-(4-phenyl-1H-1,2,3-triazole-1-yl)-α-d-ribofuranose (19i) possessed activity comparable with the standard drug. The influence of the phenyl group on carbon 3 of the carbohydrate framework is discussed.