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Natural and synthetic quinoline molecules against tropical parasitic pathologies: An analysis of activity and structural evolution for developing new quinoline-based antiprotozoal agents

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Abstract

The recent developments in the use of natural quinoline products and synthetic quinoline-based molecules as antiparasitic agents for Chagas disease (CD), African sleeping sickness (human African trypanosomiasis, HAT), and leishmaniasis (LE) are reviewed in this chapter. Classical and contemporary syntheses of quinoline derivatives are also discussed, paying attention to new green reaction conditions for classical methods such as Skraup and Friedländer syntheses, Doebner reaction or Povarov reaction, among others. Lipinski’s parameters and in silico study are briefly mentioned and applied to some quinolines active against Leishmania and Trypanosoma parasites. This chapter is focused on medicinal chemistry research with natural and synthetic quinoline molecules as antitrypanosomal agents for these parasitic infections. Carefully selected examples are discussed to underline the progress made in the development of natural and synthetic quinolines for potential therapeutic applications in CD, HAT, and LE.

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The WHO recognizes human African trypanosomiasis, Chagas disease and the leishmaniases as neglected tropical diseases. These diseases are caused by parasitic trypanosomatids and range in severity from mild and self-curing to near invariably fatal. Public health advances have substantially decreased the effect of these diseases in recent decades but alone will not eliminate them. In this Review, we discuss why new drugs against trypanosomatids are required, approaches that are under investigation to develop new drugs and why the drug discovery pipeline remains essentially unfilled. In addition, we consider the important challenges to drug discovery strategies and the new technologies that can address them. The combination of new drugs, new technologies and public health initiatives is essential for the management, and hopefully eventual elimination, of trypanosomatid diseases from the human population.
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A Gould-Jacobs cyclization enabled the synthesis of several novel, so far undescribed 3,4,6-trisubstituted quinoline derivatives. They all bear substituents which are well-suited for further transformations, e.g. carboxylic acid or ester functions, halogens, terminal alkynes and hydroxyl groups. The synthesis of a highly active 3,4-disubstituted quinolin-6-yloxyacetamide fungicide gives proof of the manifold manipulations which are possible with these interesting heterobicyclic building blocks.
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A series of new 6-(4-carboxy-3-methyl-2-phenylquinolin-6-ylsulfonyl)-3-methyl-2-phenylquinoline-4-carboxylic acids were synthesised by a one-pot reaction of dapsone, ?-ketobutyric acid, and aromatic aldehydes in the presence of CuBr2 as a catalyst. Operational simplicity, mild reaction conditions, and eco-friendly procedure make this novel protocol a promising alternative for the preparation of quinoline-4- caboxylic acid derivatives. The structures of the products were established by elemental analyses and spectroscopic data. The biological activity of the new sulfone dimers was evaluated as having the potential for use as anticancer agents.
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Novel ω-aminoacyl and -alkyl derivatives of 7-chloroquinolin-4-amine were prepared and their structures confirmed by NMR spectroscopy. Their antiprotozoal activities were examined in vitro against the sensitive NF54 strain as well as against the multiresistant K1 strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). The results were compared with the activities of clinically used drugs. Their antitrypanosomal activities were only moderate whereas their antiplasmodial activities looked very promising. Some were equal or slightly more active than chloroquine against the sensitive strain. However, in comparison to chloroquine, the activity of the new compounds was decreased much less in the resistant strain. Several possessed activity against both strains in low nanomolar concentration.
Article
Zinc(II) triflate catalyzed three-component coupling reactions of alkynes, amines and aldehydes leading to the formation of aryl/alkyl substituted quinolines has been described. Notably, the reaction proceeded efficiently and effectively without the use of ligand, co-catalyst, solvent or inert atmosphere. This robust solvent-free process operates under an ambient atmosphere and avoids the use of precious metals, hazardous solvents and harsh reaction conditions. This atom economic process eliminates the waste generated in the multistep synthesis. Additionally, a pseudo two-component Povarov reaction of amines and butanal proceeds under the same green conditions enabling the formation of 2,3-dialkyl quinolines.
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Leishmaniasis comprise a spectrum of diseases caused by protozoa parasites from the genus Leishmania, affecting millions of people worldwide, mainly in subtropical countries. Most antileishmanial drugs are highly toxic, present resistance issues or require long-term treatment. Consequently, new drugs are urgently needed. Quinoline-containing compounds have displayed an impressive array of biological properties over the years, including antileishmanial activity. In the present study, we report the synthesis and evaluation of novel quinoline derivatives (QuinDer) against Leishmania species and cytotoxic effect on mammalian cells. The ROS production and mitochondrial membrane potential analyses were also studied. The compound QuinDer1 showed activity on L. amazonensis and L. braziliensis promastigotes and this compound exhibited a strong inhibition of the proliferation of L. amazonensis amastigotes at nM concentration (IC50 of 0.0911 μM), being 139 times more active than miltefosine (IC50 of 12.7 μM), used as reference drug. This compound presents low cytotoxicity toward murine macrophages and human erythrocytes. In addition, promastigotes of L. amazonensis treated with the compound QuinDer1 present high generation of ROS levels with low alterations in mitochondrial membrane potential and maintenance of parasite membrane integrity. No substantial NO production in infected-macrophages treated with this compound was detected. These results suggest that the compound QuinDer 1 is a potent and selective antileishmanial agent by mitochondrial oxidative stress.
Article
In this study, we have investigated the antileishmanial activity of ten 7-chloro-4-quinolinylhydrazone derivatives. Among the compounds tested, compounds 2a and 2j presented activity against promastigotes (IC50 values of 52.5 and 21.1 μM, respectively) and compounds 2a and 2c were active against intracellular amastigotes (IC50 of 8.1 and 15.6 μM, respectively) of Leishmania amazonensis. The majority of compounds did not show toxicity against murine macrophages. Compound 2a exhibited low cytotoxicity to human erythrocytes and induced an oxidative imbalance in promastigote forms, reflected by an increase in the formation of reactive oxygen species (ROS) and a reduction of mitochondrial membrane potential. No alteration in the plasma membrane integrity of parasites was observed. Taken together, these results suggest that compound 2a is a selective antileishmanial agent, and preliminary observations suggest that its effects appear to be mediated by mitochondrial dysfunction.
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A practical synthesis of 4-substituted 3-aroyl quinolines via Friedländer-type reaction from readily available o-aminoaryl ketones and enaminones was developed. In the presence of ZnCl2, the reaction proceeded smoothly affording the desired products with various functional groups in moderated to good yields.
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The quinoline scaffold is present in a vast number of natural compounds and pharmacologically active substances, comprising a significant segment of the pharmaceutical market. The classical methods for the synthesis of this heterocyclic skeleton require the use of expensive starting materials and high temperature conditions. Chemists play a fundamental role in the construction of a sustainable future through the pursuit of greener chemical processes. As so, the development of new synthetic methods using more efficient energy sources and less hazardous solvents as well as renewable and eco-friendly catalysts to attain the quinoline scaffold can provide significant environmental and economic advantages. This review unveils green methods used in the synthesis of quinolones. Important green metrics are calculated for each proposed method and the statistical analysis allowed us to propose the best approaches for further investigation. The applied research is eventually unveiling the full potential of Friedländer and/or multicomponent reactions, to improve atom economy.
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This review article is an attempt to survey literature describing synthetic methods in the preparation of quinoline derivatives from N-propargylamines. Mechanistic aspects of the reactions are considered and discussed in detail.
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Human African trypanosomiasis (HAT, better called as sleeping sickness), caused by two morphologically identicalprotozoan parasite Trypanosoma bruceiis transmitted by the bite of tsetse fliesof Glossinagenus, mainly in the rural areas of the sub-Saharan Africa.HAT is one of the neglected tropical diseases and is characterized by sleep disturbance as the main symptom, hence is called as sleeping sickness. As it is epidemic in the poorest population of Africa, there is limited availability of safe and cost-effective tools for controlling the disease. Trypanosoma bruceigambiensecauses sleeping sickness in Western and Central Africa,whereasTrypanosoma bruceirhodesienseis the reason for prevalence of sleeping sickness in Eastern and Southern Africa. For the treatment of sleeping sickness, only five drugs have been approved suramin, pentamidine, melarsoprol, eflornithine and nifurtimox. Various small molecules of diverse chemical nature have been synthesizedfortargeting HAT and many of them are in the clinical trialsincluding fexinidazole (phase I completed) and SCYX-7158 (advanced in phase I). The present work has been planned to reviewvarious types of small molecules developed in the last 10 years having potent antitrypanosoma activity likely to be beneficial in sleeping sickness along withdifferent natural anti-HAT agents.
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Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP>4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (FITS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements. (C) 2012 Published by Elsevier B.V.
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The crude extracts and fractions of the Jamaican sponge Neofibularia nolitangere were examined for biological activity. The dried animal was extracted successively in three organic solvents (hexane, methylene chloride and methanol) and tested for their potential as antileishmanial, antimalarial and antimicrobial agents. Fractions of the crude methylene chloride extract demonstrated notable antimalarial properties giving percentage inhibitions of 87% and 78% respectively for fractions Y4 and Y5 at 20 μg/mL. Fractions Y4 and Z4 showed remarkable antileishmanial activity inhibiting the growth of the pathogen by 93.31% and 91.77% respectively at 20 μg/mL. No significant activity was observed in the antimicrobial assays.
Article
A silver-catalyzed formation of C-C bond for the construction of a series of polysubstituted quinolines from arylamines, aldehydes, and ketones or arylamines and 1,3-diketones has been developed. The transformation is effective for a broad range of substrates, thus enabling the expansion of constituent architectures on the heterocyclic framework. This use of a single catalytic system to mediate chemical transformations in a synthetic operation is important for the development of new atom-economic strategies and this strategy is efficient in building complex structures from simple starting materials in an environmentally benign fashion.
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A simple one-pot method for synthesizing quinoline-4-carboxylic acids (3) by the reaction of enaminones (1) and isatin (2) using the Pfitzinger reaction conditions is described. Additionally, a plausible mechanism for this transformation is presented.