The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates
Abstract
:1. Introduction
2. The Place of Quinolines as Drug Candidates in the Treatment of Leishmaniases
3. The Potential of 2-Substituted Quinolines as Antileishmanial Agents
3.1. From the Plant to Experimental Models of Leishmaniasis
3.2. From Natural Compounds to Synthetic Derivatives and Their Biological Evaluation
3.3. Formulations of the Natural 2-n-Propyl Quinoline
3.3.1. Preparation, Characterization and Biological Activity of a 2-n-Propylquinoline Salt to Improve Aqueous Solubility
3.3.2. Preparation, Characterization and Biological Activity of a Liposomal Formulation of 2-n-Propylquinoline for the Treatment of Visceral Leishmaniasis by the Intravenous Route
3.3.3. Preparation, Characterization and Biological Activity of a Formulation of 2-n-Propylquinoline with Hydroxypropyl Beta-Cyclodextrin for the Treatment of Different Manifestations of Leishmaniasis
3.4. Entering the DNDi Pipeline to Obtain Second-Generation 2-Substituted Quinolines
3.5. Structure–Activity Relationships
3.5.1. Natural Compounds and Synthetic Compounds of the First Generation
3.5.2. DNDi Series
3.6. Mechanism of Action
3.7. Drug Resistance
3.8. Orientating the Mechanism of Action of 2-Substituted Quinolines: Mechanistic Targeting for a New Series of Compounds
3.8.1. Targeting an Enzyme Involved in Host Cell Recognition
3.8.2. Conferring Chelating Properties on 2-Substituted Quinolines
3.8.3. Obtaining New Metallodrugs
3.8.4. Mechanism of Action of Dual Compounds
4. Antiviral Activities of 2-Substituted Quinolines and the Interest of this Series in Co-Infections
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Chemical Formula | In Vitro Activity Expressed as IC50 (µM) | Selectivity | In Vivo Significant Activity Monitored | References | |||||
---|---|---|---|---|---|---|---|---|---|---|
L. donovani | L. infantum | L. amazonensis | Index = CC50/IC50 | on the Leishmania sp./BALB/c Mice Model | ||||||
Oral | Sub-Cutaneous | Intralesional | Intraperitoneal | |||||||
2-n-propylquinoline | >100 (pro./i.a.) | >100 (i.a.) | / | 10 mg/kg/day × 10 (L. d.) | 85 mg/kg/day × 14 (L.a.) | 35 mg/kg/day × 15 (L.a.) | 100 mg/kg/day × 5 (L. d.) | Fournet et al., 1993 [42]; Fakhfakh et al., 2003 [55]; Desrivot et al., 2007 [58]; Campos-Vieira et al., 2008 [46] | ||
2-n-propylquinoline camphorsulfonic acid | >100 (pro.) | / | / | / | 10 mg/kg/day × 10 (L. d.) | / | / | / | Campos-Vieira et al. 2011 [59] | |
2-(2-hydroxyprop-2-enyl)quinoline | 7.8 (pro.) | 2 | 4 | > 25 | 25 mg/kg/day × 15 (L.a.); × 10 (L. i.); 12.5 mg/kg/day × 5 (L.d.) | / | / | / | Campos-Vieira et al., 2008 [46]; Fakhfakh et al., 2003 [55]; Nakayama et al., 2005 [56] | |
(E)-3-quinolin-2-yl-acrylonitrile | 38.6 (pro.); 2.4 (i.a.) | / | / | / | 12.5 mg/kg/day × 10 (L.d.) | / | / | / | Nakayama et al., 2007 [57] | |
tetraisopropyl (1-(1-(2-(quinolin-2-ylmethoxy)ethyl)-1H-1,2,3-triazol-4-yl)but-3-yne-1,1-53 diyl)bisphosphonate = Compound 99 | 0.63 (i.a.) | / | / | 2.4 | In progress | / | / | / | Mao et al., 2017 [60] | |
3-(6- chloro-7-fluoro-4-morpholino) quinoline prop-2-en-1-ol = Compound 26 g | 0.22 (i.a.) | / | / | 187.5 | 50 mg/kg/twice daily × 5 (L.d.) | / | / | / | Gopinath et al., 2013 [61] | |
Miltefosine | 3.6 (pro.); 7.5 (i.a.) | / | / | 55 | 7.5 mg/kg/day × 10 (L. i. and L.d.) | / | / | / | Campos-Vieira et al., 2008 [46]; Nakayama et al., 2005 [56]; Nakayama et al., 2007 [57] |
Compound/Formulation | In Vitro Activity on L. donovani | Cytotoxicity CC50 (µM ± SD) RAW 264.7 Cells | SI = CC50/IC50 | Treatment Regimen (Intravenous Route) × 5 Consecutive Days | Number of Mice | In Vivo Activity Reduction of Parasite Burden (%) | |
---|---|---|---|---|---|---|---|
IC50 (µM ± SD) Axenic Amastigotes | Intramacrophage Amastigotes | ||||||
2-n-PQ-Lip | 3.10 ± 0.25 Eq 2-n-PQ | 5.84 ± 0.31 Eq 2-n-PQ | 74.09 ± 6.47 Eq 2-n-PQ | 12.7 | 3 mg/kg Eq 2-n-PQ | 8 | 83.8 a |
1.5 mg/kg Eq 2-n-PQ | 8 | 32.5 a | |||||
0.75 mg/kg Eq 2-n-PQ | 8 | 5.2 | |||||
2-n-PQ-AmB-Lip | 2.02 ± 0.23 Eq 2-n-PQ | 4.50 ± 0.23 Eq 2-n-PQ | 58.31 ± 7.32 Eq 2-n-PQ | 4.3 | (1.5 mg Eq 2-n-PQ + 0.012 mg Eq AmB)/kg | 8 | 89.0 a |
0.003 Eq AmB | 0.006 Eq AmB | 0.08 Eq AmB | (0.75 mg Eq 2-n-PQ + 0.006 mg Eq AmB)/kg | 8 | 86.5 a | ||
(0.37 mg Eq 2-n-PQ + 0.003 mg Eq AmB)/kg | 8 | 10.3 | |||||
AmBisome® | 2.54 ± 0.70 Eq AmB | 1.51 ± 0.22 Eq AmB | 38.50 ± 2.37 Eq 2-n-PQ | 25.5 | 1 mg Eq AmB/kg | 8 | 88.7 a |
0.25 mg Eq AmB/kg | 8 | 27.1 | |||||
0.006 mg Eq AmB/kg | 8 | 2.3 | |||||
Blank liposomes | Inactive | Inactive | / | / | Same suspension | 10 | 5.7 |
2-n-propylquinoline (2PQ) | >100 | >100 | / | / | / | / | / |
Control (vehicle) | Inactive | Inactive | Inactive | / | 0.2 mL | 12 | 0 |
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Loiseau, P.M.; Balaraman, K.; Barratt, G.; Pomel, S.; Durand, R.; Frézard, F.; Figadère, B. The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates. Molecules 2022, 27, 2313. https://doi.org/10.3390/molecules27072313
Loiseau PM, Balaraman K, Barratt G, Pomel S, Durand R, Frézard F, Figadère B. The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates. Molecules. 2022; 27(7):2313. https://doi.org/10.3390/molecules27072313
Chicago/Turabian StyleLoiseau, Philippe M., Kaluvu Balaraman, Gillian Barratt, Sébastien Pomel, Rémy Durand, Frédéric Frézard, and Bruno Figadère. 2022. "The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates" Molecules 27, no. 7: 2313. https://doi.org/10.3390/molecules27072313