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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
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.
... Quinolines are derivatives of pyridine and are found in many biologically active natural [5,6] and synthetic [7][8][9] compounds. Their Schiff base derivatives have also been identified with various pharmaceutical activities [10,11]. ...
... The asymmetric unit of Q14 has a molecule of the ligand, an Ag(I) metal center, a trifluoromethanesulfonate molecule and a molecule of water. Coordination in this complex is via a N atom of the quinoline moiety, an imine N atom, an O atom of a trifluoromethanesulfonate, and an O atom of a water molecule forming a pseudo tetrahedral with the bond angles around the Ag(I) center lying between 93.18 (6) and 145.17 (6) • . All the complexes feature two sets of planes described by a five-member metallacycle including the quinoline imine unit (Plane 1) and by substituted phenyl ring for Q1, Q6, and Q14 and by the thiazole moiety in the structures of complexes Q7 and Q12. ...
A series of fifteen silver (I) quinoline complexes Q1–Q15 have been synthesized and
studied for their biological activities. Q1–Q15 were synthesized from the reactions of quinolinyl Schiff base derivatives L1–L5 (obtained by condensing 2 quinolinecarboxaldehyde with various aniline derivatives) with AgNO3, AgClO4 and AgCF3SO3. Q1–Q15 were characterized by various spectroscopic techniques and the structures of [Ag(L1)2]NO3 Q1, [Ag(L1)2]ClO4 Q6, [Ag(L2)2]ClO4Q7, [Ag(L2)2]CF3SO3 Q12 and [Ag(L4)2]CF3SO3 Q14 were unequivocally determined by single crystal X-ray diffraction analysis. In vitro antimicrobial tests against Gram-positive and Gramnegative
bacteria revealed the influence of structure and anion on the complexes0 moderate to
excellent antibacterial activity. In vitro antioxidant activities of the complexes showed their good radical scavenging activity in ferric reducing antioxidant power (FRAP). Complexes with the fluorine substituent or the thiophene or benzothiazole moieties are more potent with IC50 between 0.95 and 2.22 mg/mL than the standard used, ascorbic acid (2.68 mg/mL). The compounds showed a strong binding affinity with calf thymus-DNA via an intercalation mode and protein through a static quenching mechanism. Cytotoxicity activity was examined against three carcinoma cell lines (HELA,
MDA-MB231, and SHSY5Y). [Ag(L2)2]ClO4 Q7 with a benzothiazole moiety and [Ag(L4)2]ClO4 Q9 with a methyl substituent had excellent cytotoxicity against HELA cells.
... Moreover, nitrogen containing heterocyclic compounds such quinolines III, received much attention due their wide pharmacological applications [13]. The enhancement and synergistic effect of the quinoline moiety by modification of side chain at (C4 position) and/or with conjugation with other structural motifs [14,15]. For instance, hybridization of quinoline moiety with α-aminophsophonates was proved significant synergistic effect on biological activity [16]. ...
... The antibacterial activity of different chemical compounds was tested against a set of E.coli ATCC 11229, Staphylococcus aureus ATCC 25923 and human MDR pathogenic clinical strains of Klebsiella pneumonia (Kp1, Kp5, Kp8 and Kp9) [14], and E. coli (E13, E15, E16 and E17) (unpublished data), and Staphylococcus aureus (SA4) (unpublished data) which were collected from Egyptian hospitals. Bacterial strains were recovered by culturing overnight at 37°C in Nutrient agar media (Oxoid, UK). ...
... These compounds are phosphorus analogs of naturally occurring α-amino acids and therefore, are considered promising in the field of drug discovery and development [22]. Moreover, quinoline-containing heterocyclic compounds received much attention due to their wide pharmacological applications [23][24][25]. The hybridization of quinoline moiety with α-aminophsophonate is expected to have a noticeable synergistic effect on biological activity. ...
DNA gyrase and topoisomerase IV are proven to be validated targets in the design of novel antibacterial drugs. In this study, we report the antibacterial evaluation and molecular docking studies of previously synthesized two series of cyclic diphenylphosphonates (1a–e and 2a–e) as DNA gyrase inhibitors. The synthesized compounds were screened for their activity (antibacterial and DNA gyrase inhibition) against ciprofloxacin-resistant E.coli and Klebsiella pneumoniae clinical isolates having mutations (deletion and substitution) in QRDR region of DNA gyrase. The target compound (2a) that exhibited the most potent activity against ciprofloxacin Gram-negative clinical isolates was selected to screen its inhibitory activity against DNA gyrase displayed IC50 of 12.03 µM. In addition, a docking study was performed with inhibitor (2a), to illustrate its binding mode in the active site of DNA gyrase and the results were compatible with the observed inhibitory potency. Furthermore, the docking study revealed that the binding of inhibitor (2a) to DNA gyrase is mediated and modulated by divalent Mg2+ at good binding energy (–9.08 Kcal/mol). Moreover, structure-activity relationships (SARs) demonstrated that the combination of hydrazinyl moiety in conjunction with the cyclic diphenylphosphonate based scaffold resulted in an optimized molecule that inhibited the bacterial DNA gyrase by its detectable effect in vitro on gyrase-catalyzed DNA supercoiling activity.
... Heterocyclic compounds represent one of the largest groups of compounds in organic chemistry and are often part of the nucleus of many pharmaceutical and agrochemical agents (Quin and Tyrell 2010). They are also found in the structures of many natural compounds (Kouznetsov et al. 2019;Montalban 2011) with a wide range of biological activities. Quinoline is one of the most recognized heterocycles and has long been used as antimalarial (Bawa et al. 2010), antibacterial (Senerovic et al. 2020), antitubercular (Alegaon et al. 2020), antileishmanial (Chanquia et al. 2019), antitrypanosomal (Chanquia et al. 2019), anticancer (Jain et al. 2019), antioxidant (Puskullu et al. 2016) and antiviral agents (de la Guardia et al. 2018). ...
In this communication, we feature the synthesis and in-depth characterization of a series of silver(I) complexes obtained from the complexation of quinolin-4-yl Schiff base ligands ((E)-2-((quinolin-4-ylmethylene)amino)phenol La, 2-(quinolin-4-yl)benzo[d]thiazole Lb, (E)-N-(2-fluorophenyl)-1-(quinolin-4-yl)methanimine Lc, (E)-N-(4-chlorophenyl)-1-(quinolin-4-yl)methanimine Ld, (E)-1-(quinolin-4-yl)-N-(p-tolyl)methanimine Le, (E)-1-(quinolin-4-yl)-N-(thiophen-2-ylmethyl)methanimine Lf) and three different silver(I) anions (nitrate, perchlorate and triflate). Structurally, the complexes adopted different coordination geometries, which included distorted linear or distorted tetrahedral geometry. The complexes were evaluated in vitro for their potential antibacterial and antioxidant activities. In addition, their interactions with calf thymus-DNA (CT-DNA) and bovine serum albumin (BSA) were evaluated. All the complexes had a wide spectrum of effective antibacterial activity against gram-positive and gram-negative bacterial and good antioxidant properties. The interactions of the complexes with CT-DNA and BSA were observed to occur either through intercalation or through a minor groove binder, while the interaction of the complexes with BSA reveals that some of the complexes can strongly quench the fluorescence of BSA through the static mechanism. The molecular docking studies of the complexes were also done to further elucidate the modes of interaction with CT-DNA and BSA.
The Friedländer synthesis offers efficient access to substituted quinolines from 2-aminobenzaldehydes and activated ketones in the presence of a base. The disadvantage of this procedure lies in the fact that relatively few 2-aminobenzaldehyde derivatives are readily available. To overcome this problem, we report a modification of this process involving the in situ reduction of 2-nitrobenzaldehydes with Fe/AcOH in the presence of active methylene compounds (AMCs) to produce substituted quinolines in high yields. The conditions are mild enough to tolerate a wide range of functionality in both reacting partners and promote reactions not only with phenyl and benzyl ketones, but also with β-keto-esters, β-keto-nitriles, β-keto-sulfones and β-diketones. The reaction of 2-nitroaromatic ketones with unsymmetrical AMCs is less reliable, giving a competitive formation of substituted quinolin-2(1H)-ones from the cyclization of the Z Knoevenagel intermediate which appears to be favored when certain large groups are adjacent to the AMC ketone carbonyl.
Leishmaniases are endemic in various countries and parasite is developing resistance against available drugs. Thus, development of new drugs against Leishmania is an open area of investigation for synthetic organic chemist. In order to meet this challenge, a series of 2-mercaptoquinoline derivatives have been synthesized and docked into the active site of Trypanothione reductase (TryR) enzyme required for redox balance of parasite. These were screened on promastigote and intracellular amastigote stages of L. donovani and found to show high levels of antileishmanial activity together with no cytotoxicity. Some of the synthesized compounds tested here, exhibited very steady and promising leishmanicidal activity against both promastigotes & intracellular amastigotes form, and the observations have been superbly supported by the docking results.
We report herein the synthesis and biological activities (cytotoxicity, leishmanicidal, and trypanocidal) of several furanchalcone–quinoline, furanchalcone–chromone, and furanchalcone–imidazole hybrids. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis, which is the most prevalent Leishmania species in Colombia and against Trypanosoma cruzi, which is the major pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Compounds (6e, 8a–8f, 11b, and 11c) were active against both L. (V) panamensis and T. cruzi being 8e and 8f the most active compounds with an EC50 of 0.78 and 2.16 µM against L. (V) panamensis, respectively, and 0.66 and 0.72 µM against T. cruzi, respectively. Seven hybrid compounds showed better activity than meglumine antimoniate and the anti-trypanosomal activity of nine compounds were higher than benznidazole. Although these compounds showed toxicity for mammalian U-937 cells, they still have the potential to be considered as candidates for antileishmanial or trypanocydal drug development. There is not a clear relationship between the antiprotozoal activity and the length of the alkyl linker. However, we obtained higher bioactivity when the alkyl linker has nine and twelve carbon atoms. Furanchalcone-imidazole hybrids were the most active of all compounds, showing that the imidazole salt moiety is important for their biological actions.
A process for quinoline synthesis through palladium-catalyzed oxidative cyclization of aryl allyl alcohols and anilines is described.
Today, the World Health Organization recognizes 17 major parasitic and related infections as the neglected tropical diseases (NTDs). Despite recent gains in the understanding of the nature and prevalence of NTDs, as well as successes in recent scaled-up preventive chemotherapy strategies and other health interventions, the NTDs continue to rank among the world’s greatest global health problems. For virtually all of the NTDs (including those slated for elimination under the auspices of a 2012 London Declaration for NTDs and a 2013 World Health Assembly resolution [WHA 66.12]), additional control mechanisms and tools are needed, including new NTD drugs, vaccines, diagnostics, and vector control agents and strategies. Elimination will not be possible without these new tools. Here we summarize some of the key challenges in translational science to develop and introduce these new technologies in order to ensure success in global NTD elimination efforts.
We report herein the synthesis and biological activities (cytotoxicity, leishmanicidal and trypanocidal) of six quinoline-chalcone and five quinoline-chromone hybrids. The synthesized compounds were evaluated against amastigotes forms of Leishmania (V) panamensis, which is the most prevalent Leishmania species in Colombia and Trypanosoma cruzi, which is the major pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Compounds 8–12, 20, 23 and 24 showed activity against Leishmania (V) panamensis, while compounds 9, 10, 12, 20 and 23 had activity against Trypanosoma cruzi with EC50 values lower than 18 mg mL−1. 20 was the most active compound for both Leishmania (V) panamensis and Trypanosoma cruzi with EC50 of 6.11 ± 0.26 μg mL−1 (16.91 μM) and 4.09 ± 0.24 (11.32 μM), respectively. All hybrids compounds showed better activity than the anti-leishmanial drug meglumine antimoniate. Compounds 20 and 23 showed higher activity than benznidazole, the current anti-trypanosomal drug. Although these compounds showed toxicity for mammalian U-937 cells,they still have the potential to be considered as candidates to antileishmanial or trypanocydal drug development.
A series of twelve 4-methyl-2-(2-, 3- and 4-pyridinyl)quinolines 7–9 was synthesized using modified Kametani reaction protocol and their in vitro cytotoxicity was tested against human cancer cell lines MCF-7, SKBR-3, PC3, HeLa, comparing with human dermis fibroblast as non-tumor cells. In general, these molecules displayed potent anticancer properties, but also demonstrated a narrow safe margin, as it was observed for doxorubicin. Compounds 8a, 8b, 9a and 9d showed prominent selective cytotoxicity with higher IC50 values compared with reference drug doxorubicin in prostate carcinoma, cervical epithelial carcinoma and breast carcinoma (no overexpresses the HER2/c-erb-2 gene), respectively. The 4-methyl-2-(3-pyridinyl)quinoline (8a) stands out by its low unspecific cytotoxicity (IC50 = 476.69 μM) and highly exceptional selectivity for PC3 cells (IC50 = 4.40 μM) as an interesting model for antitumor drugs against prostate carcinoma. Its 4-pyridinyl analog 9a showed superior potency against HeLa cells (IC50 = 0.016 μM) and an outstanding selectivity (SI = 4168.1) compared to doxorubicin (IC50 = 3.62 µM, SI = 0.7). Analog 9d revealed potent activity (IC50 = 0.38 µM) against breast cancer MCF-7. In silico studies are also reported. ADME profiling, in silico toxicity and drug-score data of compounds 8a and 9a resulted to be favorable compared to doxorubicin.
Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually, including 875 million children in developing economies. These diseases are also responsible for over 500,000 deaths per year and are characterized by long-term disability and severe pain. The impact of the combined NTDs closely rivals that of malaria and tuberculosis. Current treatment options are associated with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Natural products have been a valuable source of drug regimens that form the cornerstone of modern pharmaceutical care. In this review, we highlight the potential that remains untapped in natural products as drug leads for NTDs. We cover natural products from plant, marine, and microbial sources including natural-product-inspired semi-synthetic derivatives which have been evaluated against the various causative agents of NTDs. Our coverage is limited to four major NTDs which include human African trypanosomiasis (sleeping sickness), leishmaniasis, schistosomiasis and lymphatic filariasis.
Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp.
A magnetic nanocatalyst of Fe3O4@SiO2/ZnCl2 was prepared by supporting ZnCl2 on silica-coated magnetic nanoparticles of Fe3O4. This recoverable catalyst was used for the synthesis of quinolines via Friedländer synthesis from 2-aminoaryl ketones and α-methylene ketones under solvent-free condition. The prepared catalyst was characterized by FT-IR, TEM, SEM, XRD, EDX, ICP-OES, VSM and BET. It was found that Fe3O4@SiO2/ZnCl2 showed higher catalytic activity than homogenous ZnCl2, and could be reused several times without significant loss of activity.
Current drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. The search for novel, effective, brain permeable, safe, and inexpensive antitrypanosomal compounds is therefore an urgent need. We have recently reported that the 4-aminoquinoline derivative huprine Y, developed in our group as an anticholinesterasic agent, exhibits a submicromolar potency against Trypanosoma brucei and that its homo- and hetero-dimerization can result in to up to three-fold increased potency and selectivity. As an alternative strategy towards more potent smaller molecule anti-HAT agents, we have explored the introduction of ω-cyanoalkyl, ω-aminoalkyl, or ω-guanidinoalkyl chains at the primary amino group of huprine or the simplified 4-aminoquinoline analogue tacrine. Here, we describe the evaluation of a small in-house library and a second generation of newly synthesized derivatives, which has led to the identification of 13 side chain modified 4-aminoquinoline derivatives with submicromolar potencies against T. brucei. Among these compounds, the guanidinononyltacrine analogue 15e exhibits a 5-fold increased antitrypanosomal potency, 10-fold increased selectivity, and 100-fold decreased anticholinesterasic activity relative to the parent huprine Y. Its biological profile, lower molecular weight relative to dimeric compounds, reduced lipophilicity, and ease of synthesis, make it an interesting anti-HAT lead, amenable to further optimization to eliminate its remaining anticholinesterasic activity.
Humans are protected against infection from most African trypanosomes by lipoprotein complexes present in serum that contain the trypanolytic pore-forming protein, Apolipoprotein L1 (APOL1). The human-infective trypanosomes, Trypanosoma brucei rhodesiense in East Africa and T. b. gambiense in West Africa have separately evolved mechanisms that allow them to resist APOL1-mediated lysis and cause human African trypanosomiasis, or sleeping sickness, in man. Recently, APOL1 variants were identified from a subset of Old World monkeys, that are able to lyse East African T. b. rhodesiense, by virtue of C-terminal polymorphisms in the APOL1 protein that hinder that parasite’s resistance mechanism. Such variants have been proposed as candidates for developing therapeutic alternatives to the unsatisfactory anti-trypanosomal drugs currently in use. Here we demonstrate the in vitro lytic ability of serum and purified recombinant protein of an APOL1 ortholog from the West African Guinea baboon (Papio papio), which is able to lyse examples of all sub-species of T. brucei including T. b. gambiense group 1 parasites, the most common agent of human African trypanosomiasis. The identification of a variant of APOL1 with trypanolytic ability for both human-infective T. brucei sub-species could be a candidate for universal APOL1-based therapeutic strategies, targeted against all pathogenic African trypanosomes.
Chagas disease is a neglected tropical disease caused by the flagellated protozoan Trypanosoma cruzi. The current drugs used to treat this disease have limited efficacy and produce severe side effects. Quinolines, nitrogen heterocycle compounds that form complexes with heme, have a broad spectrum of antiprotozoal activity and are a promising class of new compounds for Chagas disease chemotherapy. In this study, we evaluated the activity of a series of 4-arylaminoquinoline-3-carbonitrile derivatives against all forms of Trypanosoma cruzi in vitro. Compound 1g showed promising activity against epimastigote forms when combined with hemin (IC50<1 μM), with better performance than benznidazole, the reference drug. This compound also inhibited the viability of trypomastigotes and intracellular amastigotes. The potency of 1g in combination with heme was enhanced against epimastigotes and trypomastigotes, suggesting a similar mechanism of action that occurs in Plasmodium spp. The addition of hemin to the culture medium increased trypanocidal activity of analog 1g without changing the cytotoxicity of the host cell, reaching an IC50 of 11.7 μM for trypomastigotes. The mechanism of action was demonstrated by the interaction of compound 1g with hemin in solution and prevention of heme peroxidation. Compound 1g and heme treatment induced alterations of the mitochondrion-kinetoplast complex in epimastigotes and trypomastigotes and also, accumulation of electron-dense deposits in amastigotes as visualized by transmission electron microscopy. The trypanocidal activity of 4-aminoquinolines and the elucidation of the mechanism involving interaction with heme is a neglected field of research, given the parasite's lack of heme biosynthetic pathway and the importance of this cofactor for parasite survival and growth. The results of this study can improve and guide rational drug development and combination treatment strategies.
The diseases caused by African trypanosomes are of both medical and veterinary importance and have adversely influenced the economic development of sub-Saharan Africa. Moreover, so far not a single field applicable vaccine exists, and chemotherapy is the only strategy available to treat the disease. These strictly extracellular protozoan parasites are confronted with different arms of the host’s immune response (cellular as well as humoral) and via an elaborate and efficient (vector)-parasite-host interplay they have evolved efficient immune escape mechanisms to evade/manipulate the entire host immune response. This is of importance, since these parasites need to survive sufficiently long in their mammalian/vector host in order to complete their life cycle/transmission. Here, we will give an overview of the different mechanisms African trypanosomes (i.e. T. brucei as a model organism) employ, comprising both tsetse fly saliva as well as parasite-derived components, to modulate host innate immune responses thereby sculpturing an environment that allows survival and development within the mammalian host.
Chagas disease represents a serious burden for millions of people worldwide. Transmitted by the protozoan parasite Trypanosoma cruzi, this neglected tropical disease causes more than 10,000 deaths each year and is the main cause of heart failure in Latin America, where it is endemic. Although most cases are concentrated in Latin American countries, Chagasdisease has been increasingly reported in non-endemic regions, where thelow level of public awareness on the subject contributes to the growing prevalence of the disease.The available medicines are characterized by several safety and efficacy drawbacks that prevent millions of people, particularly those with advanced disease, from receiving adequate treatment.This urgent need has stimulated the emergenceof diverse initiatives dedicated to the research and development (R&D) of noveltherapeutic agents for Chagas disease. Public-privatepartnerships havebeen responsible for a significant increase in the investments in R&D programsand major advancements have been achieved over the past ten years.A number of collaborative projects have been leveraged by this organizational model, which privileges sharing of data, expertise, and resources between research institutions and pharmaceutical companies.Among the currentstrategies employed by these consortia, target-based and phenotypic screenings have achieved the most promising results.This article provides an overview onthe current status and recent advances in Chagas disease drug discovery.
This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions and the designation "natural product botanical", or "NB", to cover those botanical "defined mixtures" now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from around the 1940s to the end of 2014, of the 175 small molecules approved, 131, or 75%, are other than "S" (synthetic), with 85, or 49%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore it is considered that this area of natural product research should be expanded significantly.
An efficient method for C1-functionalised regioselective synthesis of 3-arylbenzo[f]quinoline has been demonstrated via δ-selective inferred aromatization using β-ketoester, 2-naphthylamine and aromatic aldehyde by employing 10 mol% camphorsulfonic acid as catalyst in acetonitrile at 70 °C. In this approach, two C-C bond formation will attain functionalised benzo[f]quinoline in one-pot three component reaction. In addition, the present protocol access a diverse substrate scope tolerance with good yields. Furthermore, the protocol was directly utilised for the synthesis of alkyl 2-(3-(naphthalen-2-yl)benzo[f]quinolin-1-yl)acetate, allyl 2-(3-(heteroaromatic)benzo[f]quinolin-1-yl)acetate and functionalised 1,2,3-trisubstituted benzo[f]quinoline.
Brønsted acid-catalyzed cyclization reactions of N-alkyl anilines with alkynes or alkenes in the presence of oxygen gas as an oxidant under metal- and solvent-free conditions are described. Various quinolinne derivatives...
A new synthetic protocol for the one-pot synthesis of 2-(4-hydroxybutyl)-3-(3-hydroxypropyl)quinolines and 3-(2-hydroxyethyl)-2-(3-hydroxypropyl)-quinolines based in the AB² imino-Diels-Alder reaction is reported. The protocol describes simple and efficient preparation of 2,3-disubstituted quinolines using a domino-sequential process and applying the chemical properties of cyclic enol ethers, such as 2,3-dihydrofuran and 3,4-dihydro-2H-pyran and diverse arylamines, through an imino-Diels-Alder process between an in situ generated 2-azadiene and another equivalent of the cyclic enol, catalyzed by BiCl3, and followed by the aromatization (oxidation) process guided by the MnO2.
3-Difluoroacetylated quinolines and 3-fluoroacetylated quinolines were synthesized via a visible-light-induced cascade addition/cyclization of N-propargyl aromatic amine with ethyl bromodifluoroacetate or ethyl bromofluoroacetate catalyzed by fac-Ir(ppy)3 under mild conditions. For the substrates bearing various substituents on the aniline ring and benzene ring, the reaction proceeded smoothly to give the corresponding difluoroacetylated or fluoroacetylated quinolines in moderate to high yields.
We report herein an improved Pfitzinger reaction for the synthesis of highly functionalized quinaldines from 1,3-dicarbonyl compounds, isatins and alcohols mediated by TMSCl. This synthesis involves cyclization and esterification in one-step cascade process for the formation of a carboxylate (CO2R) at the 4-position of quinaldine ring. Moreover, this procedure shows highly efficient, good functional group tolerance, operational simplicity, environment-friendly and feasibility of scale up.
A synergistic I2/amine promoted formal [4 + 2] cycloaddition of methyl ketones, arylamines, and aryl(alkyl)acetaldehydes as alkene surrogates has been established. This protocol allowed the modular synthesis of various 2-acyl-3-aryl(alkyl)quinolines, rather than 2,4-substituted quinolines. Notably, the arylamines not only participated as reactants in this reaction but also acted as indispensable catalysts to promote enamine formation. Moreover, mechanistic investigation suggested that the reaction occurred via an iodination/Kornblum oxidation/Povarov/aromatization sequence.
Highly facile, single-step synthetic approach of 3-iodoquinolines is developed for the first time from readily available 2-aminobenzophenones and terminal alkynes. The reaction involves a nucleophilic addition of terminal alkynes to 2-aminobenzophenones followed by intramolecular regioselective iodocyclization (6-endo dig) to furnish 2,4-disubstituted, 3-iodoquinolines in high yields. In case of 2,4-diaryl substitution, the products were isolated without a column chromatography
Quinolines and their derivatives are an important class of heterocyclic compounds that occur widely in natural products, drugs and biologically active compounds. A large variety of quinolines have displayed interesting physiological activities and found attractive applications as pharmaceuticals and agrochemicals. In accordance with these useful properties and related applications as above-mentioned, a number of methods have been reported for the synthesis of quinolines. Although other methods such as the Skraup, Doebner-Miller and Combes procedures have been reported, the Friedländer heteroannulation is still one of the most simple and straightforward methods used to produce poly-substituted quinolines. The Friedländer synthesis involves a condensation reaction followed by a cyclodehydration reaction between an 2-aminoaryl aldehyde or ketone and an aldehyde or ketone containing an α- methylene group. This procedure has been catalyzed by several homogeneous and heterogeneous catalysts, such as bases, Brönsted acids, Lewis acids, ionic liquids, etc.
Background: The quinoline moiety has been reported to be a privileged structure due to its presence in many drugs. It appears in alkaloids and natural products such as quinine, camptothecin or cinchonidine. The spectrum of the activity of quinoline-related compounds includes not only antimicrobial but also anticancer effects. Objective: Those active quinoline alkaloids have become the basis for a large number of synthetic drugs. Nowadays, more than a third of quinoline-derived drugs have a natural provenance. There are also a number of quinoline alkaloids that have been used extensively for treating neglected diseases in traditional medicine. Interestingly, most of the active plants predominantly populate countries that suffer most from such diseases. In this work, quinoline alkaloids that have an antimicrobial activity that might be relevant to neglected diseases are reviewed.
Solketal is derived from the reaction of acetone with glycerol, a by-product of the biodiesel industry. We report here the continuous reaction of solketal with anilines over a solid acid niobium phosphate (NbP), for the continuous generation of quinolines in the well-established Skraup reaction. This study shows that NbP can catalyse all the stages of this multistep reaction at 250 °C and 10 MPa pressure, with a selectivity for quinoline of up to 60%. We found that the catalyst eventually deactivates, most probably via a combination of coking and reduction processes but nevertheless we show the promise of this approach. We demonstrate here the application of our approach to synthesize both mono- and bis-quinolines from the commodity chemical, 4,4′-methylenedianiline.
A unique, ruthenium-catalyzed, [3 + 3] annulation of anilines with allyl alcohols in the synthesis of substituted quinolines is reported. The method employs a traceless directing group strategy in the proximal C-H bond activation and represents a one-pot Domino synthesis of quinolines from anilines.
A highly efficient I2-promoted formal [4 + 2] cycloaddition has been developed for the synthesis of 2-acylquinolines from methyl ketones and arylamines using 1,4-dithane-2,5-diol as an ethylene surrogate. Moreover, the investigation of the mechanism suggested that this reaction occurred via an iodination/Kornblum oxidation/Povarov/aromatization sequence. It is noteworthy that the arylamine substrate also played an important role in promoting the reaction.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.