Research ArticleSynthesis, Characterization, and Antileishmanial Activity ofCertain Quinoline-4-carboxylic Acids
Mazin A. S. Abdelwahid ,1 Tilal Elsaman ,2,3 Malik S. Mohamed ,4,5 Sara A. Latif,6
Moawia M. Mukhtar,6 and Magdi A. Mohamed2,7
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Neelain University, Khartoum, Sudan2Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Omdurman Islamic University, Khartoum, Sudan4Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia5Department of Pharmaceutics, Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan6Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan7Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan
Correspondence should be addressed to Mazin A. S. Abdelwahid; [email protected]
Received 30 August 2018; Revised 17 November 2018; Accepted 25 November 2018; Published 3 February 2019
Leishmaniasis is a fatal neglected parasitic disease caused by protozoa of the genus Leishmania and transmitted to humans bydifferent species of phlebotomine sandflies. ,e disease incidence continues to increase due to lack of vaccines and prophylacticdrugs. Drugs commonly used for the treatment are frequently toxic and highly expensive. ,e problem of these drugs is furthercomplicated by the development of resistance. ,us, there is an urgent need to develop new antileishmanial drug candidates. ,eaim of this study was to synthesize certain quinoline-4-carboxylic acids, confirm their chemical structures, and evaluate theirantileishmanial activity. Pfitzinger reaction was employed to synthesize fifteen quinoline-4-carboxylic acids (Q1-Q15) by reactingequimolar mixtures of isatin derivatives and appropriate α-methyl ketone. ,e products were purified, and their respectivechemical structures were deduced using various spectral tools (IR, MS, 1H NMR, and 13C NMR). ,en, they were investigatedagainst L. donovani promastigote (clinical isolate) in different concentration levels (200 μg/mL to 1.56 μg/mL) against sodiumstibogluconate and amphotericin B as positive controls. ,e IC50 for each compound was determined and manipulated sta-tistically. Among these compounds, Q1 (2-methylquinoline-4-carboxylic acid) was found to be the most active in terms of IC50.
1. Introduction
Leishmaniasis is a fatal neglected parasitic disease caused byobligate intramacrophage protozoa of the genus Leishmaniaand transmitted to humans by different species of phle-botomine sandflies [1]. Leishmaniasis is found in at least 88countries, but most cases are observed in underdeveloped ordeveloping countries [2]. According to the World HealthOrganization (WHO) estimations, 90% of global visceralleishmaniasis (VL) cases occurred in 6 countries:Bangladesh, Brazil, Ethiopia, India, South Sudan, and Sudan[3]. Around two-thirds of the VL cases every year in EastAfrican countries are reported from Sudan with estimatedannual incidence of 15,700 to 30,300 [3, 4].
,e causative agents of leishmaniasis belong to the genusLeishmania. Two different morphological forms appearduring the life cycle of these parasites. One is the flagellatedand the other is mobile promastigote, which lives in themidgut of the sandfly. Once inside the mammalian blood-stream, the promastigote converts into amastigote form,living inside the vertebrate macrophage cells [5, 6].
Leishmaniasis has traditionally been classified in threedifferent clinical types, visceral (known as Kala-Azar) (VL),cutaneous (CL), and mucocutaneous leishmaniasis (MCL),which have different immunopathologies and degrees ofmorbidity and mortality [5, 7].
VL affects vital functions and organs of the body andrepresents the most severe clinical type, showing the second
HindawiJournal of ChemistryVolume 2019, Article ID 2859637, 9 pageshttps://doi.org/10.1155/2019/2859637
highest mortality rate for a parasitic disease, after malaria[5]. ,e disease affects approximately 12 million peoplearound the world, primarily in developing regions [8].Furthermore, it is endemic in many tropical and sub-tropical regions of the world [9]. ,e risk of leishmaniasis isfurther stressed out by the sharp increase of Leishmania/HIV coinfection in many parts of the world includingEuropean countries such as Spain, Italy, France, andPortugal [10, 11].
,ere are no approved vaccines or prophylactic drugsagainst any form of leishmaniasis [12, 13]; thus, the controland management of the disease depend mainly on chemo-therapy.,e treatment is mainly based on organic pentavalentantimonial compounds, pentamidine, amphotericin B, mil-tefosine, and few other drugs [14, 15]. ,e pentavalent an-timonials have been the first-line antileishmanial agents forover 60 years, but their efficacy is reducing due to theemergence of resistance in some regions of the world [16, 17].Amphotericin B is effective against VL but it is nephrotoxic,and its use requires a hospitalization. ,e liposomal formu-lation of amphotericin B is highly effective against VL and isless toxic than the normal one, but it is much more expensivethan the other current antileishmanial drugs [8, 18, 19]. Otherdrugs like miltefosine, paromomycin, pentamidine, and flu-conazole have shown some usefulness and could be a potentialsupplement in the drugs regimen [20].
Unfortunately, all drugs used currently for treatment ofleishmaniasis are frequently toxic and highly expensive. ,eproblem of these drugs is further complicated by the de-velopment of drugs resistance in various endemic regions ofthe world [14]. In light of the above, the development of newefficient and safer antileishmanial agents is urgently needed.
A huge number of studies have been conducted toevaluate the antileishmanial activity of various plant extractsand synthetic molecules. Among the classes of moleculesthat exhibit promising antileishmanial activity are quino-lines. Quinolines are a structurally diverse group of com-pounds, with basic quinoline nucleus, that have a broadrange of biological activity and are present in differentnatural and synthetic products [21]. ,eir biological activityincludes antileishmanial, antimalarial, antibacterial, anti-fungal, anthelmintic, cardiotonic, anticonvulsant, anti-inflammatory, analgesic, and antitumor activity [22–25].Numerous quinolines have been found to have a varyingdegree of activity against leishmaniasis. A huge number ofpublications disclosing promising compounds have beenpublished in the last few years [26–35].
,e current work aims at synthesizing some quinolinederivatives and at investigating their antileishmanial activity.
2. Materials and Methods
2.1. Chemistry. All chemicals used were of commerciallyavailable reagent grade and were used without further pu-rification. Isatins were purchased from Sigma-Aldrich.Melting points were determined on Stuart melting pointapparatus (Stuart Scientific, England) and were uncorrected.,e reaction’s progress wasmonitored by precoated silica gelplates of 0.25mm thickness obtained from SD Fine-Chem
limited, India. Spots were visualized by using either UV-lamp or iodine.
Infrared (IR) spectra were recorded as KBr disk usingShimadzu IR apparatus at the Research Center, College ofScience, Khartoum University, Sudan. ,e data are givenin υ′ (cm−1). NMR spectra were determined in DMSO-d6and recorded on NMR spectrophotometer (500MHz) atKyoto University, Japan. ,e chemical shifts are expressedas δ values (ppm) relative to the internal standard, tet-ramethylsilane (TMS). Signals are indicated by the fol-lowing abbreviations: s � singlet, bs � broad singlet, d �
doublet, dd � doublet of doublet, t � triplet, q � quartet,and m � multiplet. ,e J constants were given in (Hz).Mass spectra were taken on EI-MS spectrometer at KyotoUniversity, Japan. Mass spectral data were given as m/z(intensity %).
2.1.1. General Procedure for the Synthesis of Target Molecules.Amixture of 0.5 g of the appropriate isatin derivative, 30mLof 33% w/v aqueous potassium hydroxide, and equimolaramount of ketone was heated under reflux for 15–24 hours(the reaction progress was monitored by TLC using ethylacetate : hexane mixture (3 : 2) as a mobile phase). After that,the reaction mixture was cooled and diluted with water. ,esolution was neutralized with 1M hydrochloric acid. ,eprecipitate was filtered, washed with water, dried, andrecrystallized from ethanol (Scheme 1).
2.2. Biological Evaluation
2.2.1. Preparation of the Synthesized Compounds andStandard Drugs Solutions. Sodium stibogluconate andamphotericin B (AmBisome) were used as positive controls.Stock solutions of the synthesized quinolines (10mg/mL)were prepared by dissolving 10mg of the tested com-pounds in 1mL of DMSO. Each stock solution was furtherdiluted with Roswell Park Memorial Institute (RPMI) com-plete media to obtain serial dilutions ranging from 200 μg/mLto 1.56 μg/mL.
2.2.2. Parasite Isolation and Cultivation. A confirmedpositive VL patient was subjected to lymph node aspirationfor parasite isolation. Biopsies were aseptically inoculatedinto Novy-MacNeal-Nicolle (NNN) medium. Cultures wereincubated at 25°C, and parasite growth was monitored daily.Promastigotes were transferred into tissue culture flaskscontaining RPMI media supplemented with 10% fetal calfserum (FCS) and antibiotics, streptomycin and benzylpe-nicillin. ,e medium was changed every 3 days until pro-mastigotes reached their stationary phase.
2.2.3. In Vitro Evaluation of the Antileishmanial Activity.Promastigote density was adjusted to 2 × 106 parasites/mLusing RPMI complete media. A volume of 100 μL fromparasite culture was transferred into a 96-well flat-bottomculture plate. Various concentrations of tested compoundssolutions were added (100 μL) in triplicates.
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A negative control (1% DMSO) and positive controls(sodium stibogluconate and amphotericin B) were treatedsimilarly. ,e plates were incubated at 25°C for 24 hours.Parasites were counted by using a hemocytometer. ,e IC50for each compound was determined and manipulated sta-tistically. ,e result is represented in Table 1.
2.3. Computational Studies
2.3.1. Molecular Docking. Molecular docking was carriedout based on the crystal structures of Leishmania donovanipteridine reductase, PTR1 (PDB: 2xox with a resolution of2.5 A [36]), L. donovani mitogen-activated protein kinase,MapK (PDB: 4qny with a resolution of 2.26 A [37]), L.donovani dihydroorotate dehydrogenase, DHODH (PDB:3c61 with a resolution of 1.80 A [38]), L. donovaniN-myristoyltransferase, NMT (PDB: 2wuu with a resolutionof 1.42 A [39]) and L. donovani O-acetyl serine sulfhy-drylase, AS (PDB: 3spx with a resolution of 1.79 A [40]).
Solvent molecules and cocrystallized ligands were re-moved from the proteins, and hydrogen atoms were added.,e site at which the cocrystallized ligand was present waschosen as the binding site. However, in the case of un-availability of cocrystallized ligand, the active site was de-termined using SiteFinder program embedded in MolecularOperating Environment (MOE). Preparation and energyminimization of each protein were performed with MOE(MMFF94 force field, gradient 0.01 kcal/mol A2). Each li-gand structure was built by ChemSketch and optimizedusing the MMFF force field on the MOE software [41, 42].
,e compounds set was docked on the previous target-binding sites by using AutoDock Vina software in PyRx[43, 44]. ,e docking experiment was carried out betweenthe energy-minimized ligands and the active site through agrid cube at the geometrical center of the active site. ,edocking poses were ranked according to their docking scoresas free energy of binding, and the results were exported forfurther analysis. ,e results are represented in Table 2.
2.3.2. Drug-Likeness Assessment. ,e number of rotatablebonds, topological polar surface area (TPSA) and the numberof hydrogen bond donors (HBD) and acceptors (HBA) for themost promising candidate of this study and clogP for allsynthesized compounds were estimated using Molinspirationserver (available at: http://www.molinspiration.com).
All the computational studies were carried out on awindows x64 operating system with 2.5GHz Intel Core i5processor and 8GB (RAM).
3.2. Biological Activity. ,e parasite viability curve ofcompounds Q1, Q4, Q5, and Q12 is shown in Figure 1. ,eIC50 of the synthesized quinolines and positive controls aregiven in Table 1.
3.3. Molecular Docking and Drug-Likeness Studies.Docking energies (kcal/mol) of the synthesized compoundsand drug-likeness assessment by Molinspiration for com-pound Q1 are given in Tables 2 and 3, respectively.
4. Discussion
VL is considered as one of the leading causes of morbidityand mortality in tropical countries. ,e current therapeuticoptions for leishmaniasis are limited and are fast shrinkingdue to the emergence of widespread resistance and toxicity.One of the essential approaches to develop a new candidateas an antileishmanial agent is to synthesize moleculespossessing a known scaffold with a reported antileishmanialactivity. One of these scaffolds is quinoline ring which hasbeen used extensively in the literature to produce newcompounds with potential antiparasitic agents [45–51]. As aconsequence, the current work aims at synthesizing somequinoline derivatives and at investigating their anti-leishmanial activity.
Quinoline-4-carboxylic acids are compounds of generalsynthetic interest due to their wide range of biological ac-tivities [52–54]. Among several ways to synthesize them,Pfitzinger reaction; a reaction that offers an easy and suitablesynthetic way to quinoline-4-carboxylic acids in good yieldsfrom readily available materials, shown in Scheme 1, wasemployed to synthesize the present fifteen quinoline-4-carboxylic acids (Q1-Q15) by reacting equimolar mixtureof isatin derivatives and appropriate α-methyl ketone inaqueous potassium hydroxide (33% w/v) under reflux for15–24 hours. Treatment of these salts with 1M HCl affordedthe target compounds.
TLC was used to monitor the chemical reactionsprogress, in which ethyl acetate: n-hexane (3 : 2) mixture wasused as a solvent system. ,e synthesized compounds werepurified by recrystallization from ethanol.,e purity of thesecompounds was ensured by TLC. ,e percentage yieldsranged from 30% to 95%.
,e molecular structures of the synthesized quinoline-4-carboxylic acids were confirmed on the basis of their spectraldata which were consistent with the reported data [54–56].,e infrared spectra of all synthesized compounds showed abroad band at 3419–3300 cm−1characteristic to OHstretching of carboxylic acid in addition to the presence of astrong sharp band at 1680–1710 cm−1 attributed to car-boxylic C�O stretching. Bands around 1508–1640 cm−1 and3021.80–3096.98 cm−1 corresponding to C�C and C–Haromatic stretching, respectively were also observed. Whilethe synthesized compounds with a monosubstituted ben-zene ring showed two bands around 690 and 750 cm−1 at-tributed to the out-of-plane aromatic C–H bendingvibrations, compounds with para-disubstituted benzenering revealed one band around 800–850 cm−1.
For 1H NMR, spectra of the synthesized compounds werefound to be in consistence with the suggested structures.Furthermore, the number of the integrated protons in thespectra matched the expected number of aromatic protons ineach case. ,e spectra showed a broad singlet at δ 14 ppmintegrated to one proton most likely assigning to the mostdeshielded acidic COOH proton. Compounds Q3, Q4, Q9,Q11, Q14, and Q15 spectra displayed a singlet at δ 2.9 ppm(for compound Q9) and at 3.8 ppm (for the remaining) in-tegrated to three protons corresponding to the –CH3 and–OCH3 protons, respectively. A highly deshielded singlet at
Journal of Chemistry 5
9.95, 10.02, and 9.78 for compounds Q7, Q8, and Q13, re-spectively, corresponding to phenolic OH was observed.
,e 13C NMR spectra of all compounds displayed asignal resonating around δ 167 ppm, which disappeared inDEPT-90 and 135 spectra, relating to the carboxylic acidcarbonyl carbon. Moreover, two signals resonating around δ155 and δ 148 ppm, for all compounds that disappeared inDEPT spectra are attributed to the aromatic carbon atomsdirectly attached to quinoline’s nitrogen atom. As expected,all DEPT-135 spectra did not show a negative peak in-dicating the absence of methylene carbons in the synthesizedcompounds. As a result, the DEPT-90 and DEPT-135spectra found to be identical for those compounds that haveno methyl groups.
Although the molecular ion peak [M+] varied in in-tensity, it was evidenced for all analyzed synthesizedcompounds. A special peak at m/z � 154, corresponding to
a common fragment for all synthesized compounds, rep-resented the base peak with an exception of compoundQ14in which [M+] was the base peak. Interestingly, the syn-thesized molecules with a bromo substituent displayed acharacteristic 1 : 1 ratio between [M+]:[M+2], which is inagreement with the bromine natural isotopic distribution(50 : 50).
As a preliminary investigation, the antileishmanial effectof the synthesized quinolines was assessed on L. donovanipromastigotes. L. donovani is the causative agent of VLwhich is the most severe form of leishmaniasis, especially inSudan and other developing countries [57].
,e tested parasite was subjected to different concen-tration levels of the synthesized compounds to determineIC50, the compound concentration causing 50% inhibition ofthe parasitic growth.,e results of the antileishmanial activityof the tested compounds along with the standard drugs aspositive controls are presented in Table 1 and Figure 1.
Compounds Q4, Q5, Q6, and Q14 exhibited moderateto weak antileishmanial activity against L. donovani pro-mastigotes, with IC50 values 27.03, 103, 84.49, and 31.9 µg/mL, respectively (Table 1). Compound Q12 revealed acomparable activity to that of the standard amphotericin B
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Figure 1: ,e parasite viability curve of (a) compound Q1, (b) compound Q4, (c) compound Q5, and (d) compound Q12.
Table 3: Drug-likeness assessment by Molinspiration for com-pound Q1.
with IC50 values 17.19 and 14.70 µg/mL, respectively. In-terestingly, compound Q1 (IC50 � 1.49 µg/mL) was found tobe five times more potent than the standard drug sodiumstibogluconate (IC50 � 8.06 µg/mL) and ten times morepotent than amphotericin B (IC50 � 14.70 µg/mL). However,the introduction of a nitro group at C-6 of the quinoline ringof compound Q1 abolishes the activity (Q9).
Regarding 2-phenyl quinoline-4-carboxylic acid series,there is a good correlation between the lipophilicity of thesemolecules and the biological activity. Nonetheless, com-pound Q5 has a good lipophilicity (clogP � 4.45), and itsIC50 is higher than other analogues with comparable lip-ophilicity (Q5 IC50 � 103 µg/mL compared with Q4 clogP:4.48 with IC50 � 27.03 µg/mL), confirming that the presenceof electron-withdrawing group in C-6 quinoline ring isessential for the activity of these compounds.
Among these compounds, compoundQ6 has the highestlipophilicity (clogP � 5.23) with a bromosubstituent at C-6suggesting that it has the lowest IC50 of these analoguestheoretically. However, the activity of Q6 (IC50 � 84.49 µg/mL) is much lower than those of Q4 and Q12 (clogP � 4.48,IC50 � 27.03 and clogP � 4.38, IC50 � 17.19 µg/mL, re-spectively). It is worth noting that compound Q6 violatesone of the Lipinski’s rule parameters (Q6 clogP> 5). ,isviolation may contribute to the reduction of the penetrativeability of this compound to the cell membrane of the parasiteand thus decreasing its activity. It can reasonably be con-cluded that the optimum clogP of these compounds (2-phenylsubstituted quinoline) to be active is between 4.20 and4.50. It can be proposed that the presence of an electron-withdrawing group in C-6 of the quinoline ring increases theelectron-deficiency of this moiety making it a good candi-date for a charge transfer interaction with the target.
,e Q15 violation of Lipinski’s rule (clogP> 5.64) maycontribute to its weaker activity (IC50 � 208 µg/mL) whencompared to the 2-naphthyl analogue compound Q14 (IC50� 31.9 µg/mL).
In general, for all synthesized compounds together, thereis no constant pattern that correlates the activity with thecalculated log P values. ,is indicates that other factors mayinfluence the activity. A molecular docking analysis has beencarried out to assess the molecular interaction patterns of thesynthetic compounds in L. donovani targets and to de-termine the best-ranking poses of the compounds that ex-hibit the best affinity values. ,e synthetic quinolines weredocked into 5 leishmanial targets that have been previouslyidentified as potential drug targets. ,e docking energies(kcal/mol) of the synthesized compounds are summarized inTable 2.
Knowing that promastigote is not an adequate bi-ological stage to identify promising antileishmanial com-pounds, in silico studies were conducted to evaluate theactivity of these compounds on selected targets known tobe expressed in amastigotes and druggable to quinolines. Itwas hoped that promising docking results might be apotential evidence for the activity of these compoundsagainst amastigotes. All compounds were docked nicely onthe active site for each target with satisfactory bindingenergies (−6.3 to −10.4 kcal/mol).
Further evaluation of the most promising compound ofthis study (compound Q1) in terms of prediction of its oralbioavailability based on Lipinski’s rules and Veber’s pa-rameters was conducted computationally using Molinspi-ration server [58, 59]. From these studies, compoundQ1wasfound to be in complete agreement with Lipinski’s rule offive and Veber’s parameters. ,us, it is suggested to have agood GIT absorption and a good oral bioavailability (Ta-ble 3). Furthermore, the values of Lipinski’s rule parametersand Veber’s parameters of this compound are in the lowestranges making this compound a good candidate for furthermodification without major violations of these rules. Withall these findings, compound Q1 could be envisioned as apromising and potential lead compound for antileishmanialdrug discovery projects.
5. Conclusion
Fifteen 2-substituted quinoline-4-carboxylic acid analogues(Q1-Q15) were synthesized, their chemical structures werespectrally confirmed, and their activities were evaluatedagainst L. donovani promastigotes using two standard drugs.Among these compounds, Q1 (2-methylquinoline-4-car-boxylic acid) was found to be the most active. Virtualscreening revealed that Q1 and possibly some other testedcompounds might have strong interactions with importantbinding sites of multiple druggable targets in amastigotes.
Data Availability
,e data used to support the findings of this study areavailable from the corresponding author upon request.
Conflicts of Interest
,e authors declare that they have no conflicts of interest.
Acknowledgments
,e authors wish to thank Prof. Ken-ichi Yamada (GraduateSchool of Pharmaceutical Sciences, University of Tokush-ima, Japan) for his help.
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