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South African Journal of Chemistry

versão On-line ISSN 1996-840X
versão impressa ISSN 0379-4350

S.Afr.j.chem. (Online) vol.71  Durban  2018

http://dx.doi.org/10.17159/0379-4350/2018/v71a23 

RESEARCH ARTICLE

 

Synthesis, Antiplasmodial and Antitrypanosomal Evaluation of a Series of Novel 2-Oxoquinoline-based Thiosemicarbazone Derivatives

 

 

Oliver T. DarrelI; Siyabonga T. HulusheI; Thanduxolo E. MtshareI; Richard M. BeteckI; Michelle IsaacsII; Dustin LamingII; Heinrich C. HoppeII, III; Rui W.M. KrauseI, II; Setshaba D. KhanyeI, II, IV, *

IDepartment of Chemistry, Rhodes University, Grahamstown, 6140, South Africa
IICentre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown, 6140, South Africa
IIIDepartment of Biochemistry and Microbiology, Rhodes University, Grahamstown, 6140, South Africa
IVFaculty of Pharmacy, Rhodes University, Grahamstown, 6140, South Africa

 

 


ABSTRACT

Herein a series of novel thiosemicarbazones (TSCs) derived from 2-oxoquinoline scaffold is reported, and the target compounds have been successfully synthesized and characterized using standard spectroscopic techniques. The in vitro biological activities of synthesized molecules were evaluated against Plasmodium falciparum malaria parasites (strain 3D7), Trypanosoma brucei brucei parasites (strain 427) and HeLa cells. All the compounds displayed modest or no activity at a concentration of 20 μΜ and percentage viability of >50 % was often observed. Except for compound 9o, none of the final compounds exhibited cytotoxic effects against HeLa cells at 20 μΜ.

Keywords: Trypanosoma brucei, trypanosomiasis, Plasmodium falciparum, thiosemicarbazones, 2-oxoquinoline.


 

 

1. Introduction

Malaria, an infectious parasitic disease, is a major health risk in many developing countries worldwide.1 Despite tremendous progress over the last two decades, in 2017 there were 216 million cases of malaria infection, with an estimated 445 000 deaths, 90 % of which occur in sub-Saharan Africa.1,2 Currently, it is estimated that almost 3.2 billion people globally are at risk of contracting the disease.3 This is further aggravated by the widespread drug and multidrug resistant Plasmodium falciparum parasite, the main cause of infection in humans, to almost all antimalarial drugs that are in clinical use.4 In the absence of an effective malaria vaccine, the need to discover and develop new antimalarial drugs, with unique structural motifs and new mode of action, that are safe and effective against highly resistant parasites is imperative.4,5

On other hand, human African trypanosomiasis (HAT), commonly referred to as a sleeping sickness, is caused by protozoan parasites of the genus Trypanosoma, and the two species that are transmitted to humans by blood-feeding tsetse flies (Glossina spp.) are Trypanosoma brucei gambiense and Trypanosoma "rucei rhodesiense.6,7Up to 70 million people, in various parts of the 36 countries in Africa where the disease is endemic, are at risk of infection.6 While the cases of HAT in Africa have been reasonably low, in 2015 an estimated 3000 new infections of East and West African trypanosomiasis were reported to the World Health Organisation (WHO).8 Regrettably, in pregnant women or those of child-bearing age, the disease causes infertility and abortion, and it is invariably fatal if left untreated.8 Currently, only a handful of drugs are available for the treatment of HAT, and are utilized based on the causative trypanosome species and stage of the disease.8 For example, pentamidine and suramin are recommended for treatment of the acute initial stage of T. b. gambiense, while a combination of nifurtimox-eflornithine and melarsoprol are deployed for the secondary stage of the disease. For T. b. rhodesiense, suramin is a preferred drug for treatment of the initial stage of the disease, while melarsoprol is reserved for secondary stage chemotherapy.9 However; these drugs have shortcomings and some of them are associated with life-threatening side effects that have prompted the scientific community to search for new compounds with desirable safety margins and drug-like properties to replace them.

Thiosemicarbazones are a class of compounds which have enjoyed significant attention due to their broad-spectrum of biological activities, including antibacterial, antiprotozoal, antifungal, antiviral and antitumour activity.10 Quinoline and related derivatives, on the other hand, are useful compounds with diverse pharmaceutical applications, and some have even reached markets for treatment of various ailments.11 The 2-oxo-quinoline (2-OCQ), which belongs to a quinoline family, is an interesting naturally occurring scaffold to attach new moieties or bioactive groups and it has been widely used as a 'parental' framework to synthesize a variety of molecules with a wide range of biological activities such as antitubercular, anti-inflammatory, antifungal and antileishmanial activity.12-15 For example, oxoquinoline-derived thiosemicarbazones I and III (Fig. 1) were found to exhibit good antiproliferative activity against the HCT116 cell line.16

In our pursuit of developing biologically relevant molecules, that could address some of the problems associated with infections caused by protozoan parasites, we are interested in exploring a class of 2-oxoquinoline-derived thiosemicarbazone derivatives as antiplasmodial and antitrypanosomal agents. To the best of our knowledge, there has been no report on the anti-plasmodial and antitrypanosomal properties of these compounds in literature. To this end, in this study we report on the synthesis of quinoline-derived thiosemicarbazones and their in vitro bioassay screening against P. falciparum 3D7 strain and T. b. brucei (strain 427) as well as cytotoxicity evaluation against HeLa cell lines.

 

2. Results and Discussion

2.1. Synthesis

The synthesis of target quinoline-derived thiosemicarbazone derivatives is outlined in Scheme 1. Commercially available anilines 1a-c were treated with a solution of acetic acid and acetic anhydride (1:1 mole ratio) under reflux to generate the corresponding acetanilides 2a-c in moderate yields.17 The Vilsmeier-Haack reaction18 involving the condensation of resultant acetanilides 2a-c with Ν,Ν-dimethylformamide (DMF), in the presence of phosphorusoxychloride (POCl3), was then used to produce 2-chloroquinoline-3-carbaldehyde derivatives 3a-c.18

The next step involved accessing the desired key intermediates, 2-oxoquinoline-3-carbaldehyde derivatives 4a-d, via a previously reported literature methods.19 Thus, the hydrolytic reaction of 3a-c in 70 % acetic acid aqueous solution resulted in quinolinone derivatives 4a-c, which were obtained in yields ranging from 38-62 %. To access compounds 4d, commercial available 2-chloroquinoline-3-carbaldehyde was reacted, under similar reaction conditions as in the synthesis of 4a-c, to yield the desired compound 4d in 69 % yield. With the desired key intermediates (4a-c) in hand, propargylation reaction using propargyl bromide yielded propargyl quinoline aldehydes 5a-c, which were then further reacted with appropriate azides, under the copper-catalyzed azide-alkyne cycloaddition (CuAAC) conditions,20-23 to form 1,4-disubstituted-1,2,3-triazoles quinoline aldehydes 6a-c in yields ranging from 42-61 %.

Similarly, reacting the key intermediates 4a-c with substituted benzylbromides and 7-chloro-N-(2-chloropropyl)quinolin-4-amine yielded quinoline aldehydes 7a-f and 8b in moderate yields, respectively. Compound 8a could not be isolated in its pure form, and instead it was reacted with thiosemicarbazide (step viii) as crude product to form the desired quinoline-derived thiosemicarbazone 9n. Lastly, all the quinoline aldehydes 5a-c, 6a-c, 7a-f and 8b were then subjected to the Schiff base condensation reaction with commercially accessible thiosemicarbazide in refluxing MeOH or EtOH to give rise to the desired 2-oxoquinoline-based thiosemicarbazone derivatives 9a-r (Table 1) in moderate to excellent yields.24-26 All the intermediates and target compounds were fully characterized by analytical and spectroscopic techniques.

 

 

2.2. In Vitro Biological Evaluation

The prepared target compounds were evaluated in vitro for antiplasmodial activity against the chloroquine sensitive (CQS) 3D7 P. falciparum, the trypanosomal subspecies responsible for nagana T. b. brucei, and for cytotoxicity evaluation using a human cervix adenocarcinoma (HeLa) cell line. Chloroquine (CQ) was included as a positive control for P. falciparum and pentamidine (PMD) was employed for T. b. brucei assays while emetine (EMT) was a positive control drug for HeLa cells. The screening assay was done using the malaria parasite lactate dehydrogenase Pf(pLDH), T. b. brucei and HeLa cell resazurin assays that were performed in duplicates using 20 mM final concentrations of each compound. The percentage cell viability results upon exposure of P. falciparum, T. b. brucei and HeLa cells to the compounds are displayed in Table 2.

 

 

The tested compounds (Table 2) exhibited no cytotoxic effects (percentage viability >64 %) as measured by the viability of HeLa cell lines at a concentration of 20 μΜ, the exception is compound 9o which reduced HeLa cell viability to 6.6 %. Excluding compounds 9m, 9n and 9o, which reduced the percentage parasite viability to below 20 %, none of the tested target compounds displayed desirable potency at the concentration of 20 μΜ. These compounds were evaluated further to determine the corresponding IC50 values (Fig. 2) against the 3D7 strain of the parasite P. falciparum. And while 9m emerged as inactive, compounds 9n and 9o displayed notable activity with the corresponding IC50 values of 2.09 and 1.79 μΜ, respectively. These data suggest that the observed antiplasmodial activity may be related to the presence of aminoquinoline moiety in each molecule, which is known to bind with haem, thus preventing the formation of haemozoin. However, the corresponding quinoline aldehyde intermediates 6c and 8b were ineffective (data not included) at the maximum tested concentration (20 mM) suggesting that enhanced activity of 9n and 9o could be attributed to the contribution of the thiosemicarbazone and 4-aminoquinoline fragments.27

Similarly, in terms of antitrypanosomal activity, none of the tested compounds exhibited appreciable activity except compounds 9n and 9o, which reduced the viability of trypanosomes (t. b. brucei) at 20 μΜ to 12.7 % and 12.8 %, respectively. Since compound 9o showed a significant cytotoxic effect at 20 μΜ, only compound 9n was further screened to determine the corresponding IC50 value (Fig. 3). Despite significant growth inhibition as measured by the viability of trypanosomes, compound 9n was found to be inactive with IC50 value of 167.7 μΜ.

 

3. Conclusion

In summary, a series of thiosemicarbazone derivatives 9a-r based on the 2-oxoquinoline structural motif have been prepared in moderate to excellent yields and their structural integrity confirmed using various spectroscopic techniques. Despite the poor antiplasmodial and antitrypanosomal activity of the majority of the tested compounds, the promising potency of 9n and 9o provides an avenue for further in-depth investigation of these bi-quinoline thiosemicarbazone compounds as a new family of quinoline-based anti-infective agents. Apart from compounds 9m, 9n and 9o, which exhibited weak to good activity with IC50 (T b. brucei) = 167.7 μΜ and IC50s(Pf) = 2.09 and 1.79 μΜ values, the rest of compounds were inactive and parasite percentage viabilities of >50 % were often observed. As determined by the HeLa cell line, the majority of these compounds showed no significant toxicity.

 

4. Experimental

4.1. General

All commercially available chemicals and reagents were purchased from Sigma-Aldrich (Pty) Ltd and Merck (Pty) Ltd, and were used without further purification unless stated otherwise. The progress of reactions were monitored by analytical thin layer chromatography (TLC) using Merck F254 silica gel plates (supported on aluminium), which were visualized under ultraviolet (UV 254 and 366 nm) light or, where necessary, stained in iodine flask. The crude compounds were purified by flash column chromatography using Merck Kieselgel 60 A: 70-230 silica gel mesh or by preparative thin-layer chromatography (PTLC) using Merck 60GF254 silica gel coated on glass plates (2.0 X 200 X 200 mm). The 1H and 13CNMR spectra were recorded on either a Bruker Fourier 300 or a 400 MHz spectrometer. Spectra were recorded in deuterated solvents: CDCl3-d6 and DMSO-d6. All chemical shift values are reported in parts per million (ppm) referenced to residual solvent resonances (CDCl3 δH 7.26, δC77.2; DMSO δH 2.50, δC 39.5). The coupling constants are given in Hertz. High resolution mass spectrometry was performed on a Waters Synapt G2 TOF instrument with an ESI source, University of Stellenbosch. Measurement of the melting points was carried out using a Reichert hot stage microscope (Protea Holdings Ltd.) and uncorrected. Elemental microanalysis was performed on Elementar Analysensysteme varioMICRO V1.6.2 GmbH analysis system.

4.2. General Procedure for Synthesis of Thiosemicarbazone Compounds 9a-r

An appropriate starting 2-oxoquinoline-3-carbaldehyde (0.081 g, 0.5 ), and thiosemicarbazide (0.5 mmol) were mixed in methanol (25 mL) and heated to 80 °C for 10 h. After reaction completion, the resulting product was allowed to cool to ambient temperature and resulted in the formation of a precipitate, which was filtered, washed with ice-cold MeOH and dried to give the desired products.

(E)-2-((2-oxo-1,2-dihydroquinolin-3-yl)methylene)hydrazinecarbo-thioamide (9a): 70 % yield; yellow solid; mp 290-293 °C (Lit28 296 °C); δH(300 MHz; DMSO-d6): 12.1 (1H, s, N(1)H), 11.7 (1H, s, N(11)H), 8.83 (1H, s, H4), 8.76 (1H, s, H9), 8.32 (1H, br s, NHH), 8.27 (1H, s, H4), 8.11 (1H, br s, NHH), 7.64 (1H, dd, J = 1.1 and 8.0 Hz, H5), 7.52 (1H, ddd, J = 1.4,7.3 and 9.2 Hz, H6), 7.30 (1H, dd, J = 0.8 and 8.0 Hz, H8), 7.22 (1H, ddd, J = 0.9, 7.3 and 9.1 Hz, H7) ppm; δC (75 MHz, DMSO-d6): 178.1, 161.0, 139.0, 136.8, 135.2, 131.1, 128.6,125.4,122.5,119.3,115.3 ppm; vmax(neat, cm-1): 3291 (NH), 3173 (NH), 1638 (C=O), 1533 (C=s), 851 (C-S); HRMS (ESI) m/z calcd for C11H10N4OS 246.0575, found 247.0662 [M+H]+; Anal. calcd for C11H10N4OS0.125H2O: C, 53.16; H, 4.16; N, 22.54; S, 12.90 %. Found: C, 53.18; H, 3.95; N, 22.54; S, 12.96 %.

(E)-2-((8-Methyl-2-oxo-1,2-dihydroquinolin-3-yl)methylene)hydra-zinecarbothioamide (9b): 63 % yield; yellow solid; mp 246-248 °C; dH(300 MHz; DMSO-d6): 11.6 (1H, s,N(1)H), 11.2 (1H, s,N(11)H), 8.76 (1H, s, H9), 8.29 (2H, s, NHh), 8.28 (1H, s, H4), 8.01 (1H, br s, NHH),7.50(1H,d, J =7.8Hz,H5),7.37(1H,d, J =7.5Hz,H7),7.14 (1H, t, J = 8.0 Hz, H6), 2.43 (3H, s, CH3) ppm; δC(75 MHz, DMSO-d6): dC 178.1,161.5,137.3,136.7,135.8,132.3,126.7,125.0, 123.6, 122.2, 119.3, 17.2 ppm; vmax(neat, cm-1): 3269 (NH), 3154 (NH), 1645 (C = O), 1531 (C=S), 856 (C-S); HRMS (ESI) m/z calcd for C12H12N4OS: 260.0732, found 261.0808 [M+H]+; Anal. calcd for C12H12N4OS-0.75H2O: C, 52.64; H, 4.97; N, 20.46; S, 11.71 %. Found: C, 52.61; H, 4.97; N, 20.48; S, 11.57 %.

(E)-2-((6-Methyl-2-oxo-1,2-dihydroquinolin-3-yl)methylene)hydra-zinecarbothioamide,(9c): 60 % yield; orange solid; mp 248-250 °C; δH(300 MHz; DMSO-d6): 11.9 (1H, s,N(1)H), 11.6 (1H, s,N(11)H), 8.68 (1H, s, H9), 8.29 (1H, br s, NHH), 8.27 (1H, s, H4), 8.07 (1H, s, NHH), 7.27 (3H, m, H5,H7 and H8) 2.33 (3H, s, CH3) ppm; δC(75 MHz, DMSO-d6): δ 178.1,160.9,137.0,136.9,134.7,132.3, 131.3,127.9, 125.2, 119.2,115.1, 20.4 ppm; vmax(neat, cm-1): 3256 (NH), 3148 (NH), 1525 (C=N), 1646 (C=N), 1208 (C=S), 863 (C-S); HRMS (ESI) m/z calcd for C12H12N4OS [M+H]+ 260.0732, found 261.0823; Anal. calcd for C12H12N4OS0.75H2O: C, 52.64; H, 4.97; N, 20.46; S,11.71 %. Found: C, 52.51; H, 5.08; N, 20.13; S, 11.50 %.

(E)-2-((6-Methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)hydra-zinecarbothioamide (9d): 69 % yield; orange solid; mp 255-256 °C (Lit.29 258-260 °C); dH(300 MHz; DMSO-d6): 11.8 (1H, s, N(1)H), 11.6 (1H, s, N(11)H), 8.72 (1H, s, H9), 8.31 (1H, br s, NHH), 8.27 (1H, s, H4), 8.05 (1H, br s, NHH), 7.26 (1H, d, J = 8.9 Hz H8), 7.18 (1H, dd, J = 2.8 and 8.9 Hz, H7), 7.12 (1H, d, J = 2.8 Hz, H5), 3.71 (3H,s,CH3) ppm; dC(75 MHz, DMSO-d6): 178.1, 160.5, 154.4, 136.8, 134.7, 133.6, 125.6, 120.5, 119.7, 116.5, 109.2, 55.4 ppm; vmax(neat, cm1): 3392 (NH), 3160 (NH), 1647 (C=O), 1530 (C=S), 840 (C-S); HRMS (ESI) m/z calcd for C12H12N4O2S: 276.0681, found 277.0747 [M+H] + . Anal. Calcd for C12H12N4O2S: C, 52.16; H, 4.38; N, 20.28; S, 11.60. Found (%): C, 52.11; H, 4.28; N, 20.23; S, 11.57 %.

(E)-2-((1-Benzyl-2-oxo-1,2-dihydroquinolin-3-yl)methylene)hydra-zinecarbothioamide (9e): 42 % yield; yellow solid; mp 222-224 °C; δH(400 MHz; DMSO-d6): 11.7 (1H, s, N(11)H), 8.86 (1H, s, H9), 8.39 (1H, s, H4), 8.34 (1H, br s, NHH), 8.14 (1H, br s, NHH), 7.73 (1H, dd, J = 1.2 and 7.8 Hz, H5), 7.53 (1H, ddd, J = 1.4,7.5 and 8.6 Hz, H6), 7.43 -7.18 (7H, m, Ar-Hs), 5.57 (2H, s, H1a) ppm; δC(101 MHz, DMSO-d6): 178.1, 160.6, 138.9, 137.0, 135.7, 134.7, 131.3,129.6,128.6,127.1,126.5,124.5,122.7,120.2,115.2,45.0 ppm; vmax(neat, cm1): 3201 (NH), 3147 (NH), 1626 (C = O), 1517 (C=N), 1207 (C=S), 855 (C-S); HRMS (ESI) m/z calcd for C18H16N4OS 336.1045, found 337.1136 [M+H]+; Anal. calcd for C18H16N4OS: C, 64.26; H, 4.79; N, 16.65; S, 9.53. Found: C, 65.16; H, 5.86; N, 14.99; S, 8.63 %.

(E)-2-((1-(4-Nitrobenzyl)-2-oxo-1,2-dihydroquinolin-3-ylyl)methy-lene)hydrazinecarbothioamide (9f): 52 % yield; yellow solid; mp 235-237 °C; dH(400 MHz; DMSO-d6): 11.7 (1H, s, N(11)H), 8.89 (1H, s, H9), 8.38 (1H, s, H4), 8.36 (1H, br s, NHH), 8.20-8.16 (2H, m, H3' and H5'), 8.15 (1H, br s, NHH), 7.76 (1H, d, J = 7.6 Hz, H8), 7.54 (1H, t, J = 8.7 Hz, H6), 7.37 (1H, d, J = 8.7 Hz, H5), 7.31 (2H, t, 7.4 Hz, H7), 5.70 (2H, s, H1a) ppm; δC(101 MHz, DMSO-d6): 178.1, 160.6, 146.6, 144.6, 138.7, 136.8, 135.0, 131.5, 129.8, 127.8, 124.6, 123.8, 123.0, 120.3, 115.3, 44.9 ppm; vmax(neat, cm-1): 3216 (NH), 3148 (NH), 1633 (C=o), 1516 (C=N), 1203 (C=S), 850 (c-s); HRMS (ESI) m/z calcd for C18H13N5O3S 381.0896, found 382.0968 [M+H]+; Anal. calcd for C18H13N5O3S-0.5CH3OH: C, 56.19; H, 3.82; N, 17.71; S, 8.11 %. Found: C, 56.61; H, 3.91; N, 17.38; S, 8.34 %.

(E)-2-((1-Benzyl-6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methy-lene)hydrazinecarbothioamide (9g): 41 % yield; yellow solid; mp 232-234 °C, δΗ(400 MHz; DMSO-d6): δ 11.7 (1H, s, N(11)H), 8.81 (1H,s,H9), 8.38 (1H, s, H4), 8.36 (1H, br s, NHH), 8.09 (1H, br s, NHH), 7.36-7.27 (3H, m, H5,H7 and H8), 7.25-7.15 (5H, m, H2',H3',H4',H5' and H6'), 5.57 (2H, s, H1a), 3.79 (3H, s, CH3) ppm; δC(101 MHz, DMSO-d6): 178.1, 160.1, 154.4, 137.1, 136.6, 134.3, 133.5, 128.6, 127.0, 126.5, 124.9, 120.9, 120.0, 116.6, 110.8, 55.4, 45.0 ppm; vmax(neat, cm-1): 3275 (NH), 3157 (NH), 1635 (C=O), 1518 (C=N), 1202 (C=S), 869 (C-S); HRMS (ESI) m/z calcd for C19H18N4O2S: 366.1150, found 367.1213 [M+H]+; Anal. calcd for C19H18N4O2S-0.25H2O; C, 61.52; H, 5.03; N, 15.10; S, 8.64 %. Found: C, 61.37; H, 4.92; N, 15.03; S, 8.72 %.

(E)-2-((6-Methoxy-1-(4-nitrobenzyl)-2-oxo-1,2-dihydroquinolin-3-yl )methylene)hydrazinecarbothioamide (9h): 57 % yield; yellow solid; mp 238-240 °C; δH(400 MHz; DMSO-d6): 11.7 (1H, s, N(11)H), 8.85 (1H, s, H4), 8.37 (1H, br s, NHH), 8.17 (2H, d, J = 8.8 Hz, H3'and H5'), 8.10 (1H, br s, NHH), 7.45 (2H, d, J = 8.8 Hz, H2 and H6'), 7.31 (1H, d, J = 9.3 Hz, H8), 7.24 (1H, d, J = 2.9 Hz, H5), 7.17 (1H, dd, J = 2.9 and 9.2 Hz, H7), 5.68 (2H, s, H1a), 3.80 (3H, s, CH3) ppm; dC(101 MHz, DMSO-d6): 178.1, 160.1, 154.6, 146.6, 144.7, 136.9, 134.5, 133.3, 127.7, 124.9, 123.8, 121.0, 120.1, 116.4, 111.8,55.4,44.8 ppm; vmax(neat, cm-1): 3215 (NH), 3155 (NH), 1636 (C=O), 1511 (C=N), 1206 (C=S), 860 (C-S); HRMS (ESI) m/z calcd for C19H17N5O4S: 411.1001, found 412.0810 [M+H]+; Anal. calcd for C19H17N5O4S: C, 55.47; H, 4.16; N, 17.02; S, 7.79 %. Found: C, 55.32; H, 4.28; N, 17.08; S, 7.97 %.

(E)-2-((1-Benzyl-6-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methy-lene)hydrazinecarbothioamide (9i): 38 % yield; yellow solid; mp 236-238 °C; δH(400 MHz; DMSO-d6): 11.7 (1H, s, N(11)H), 8.79 (1H,s,H9), 8.38 (1H, s, H4), 8.33 (1H, br s, NHH), 8.14 (1H, br s, NHH), 7.51 (1H, d, J = 1.5 Hz, H5), 7.35 (1H, dd, J = 1.6 and 8.6 Hz, H7), 7.32-7.27 (3H, m, H8,H2 and H6), 7.25-7.17 (3H, m, H3VH4, and H5'), 5.54 (2H, s, H1a), 2.34 (1H, s, CH3) ppm; dC(101 MHz, DMSO-d6): 178.1, 160.5, 137.1, 137.0, 136.6, 134.5, 132.5, 131.7, 129.1, 128.6, 127.0, 126.5, 124.5, 120.1, 115.2, 44.9, 20.0 ppm; vmax(neat, cm-1): 3191 (NH), 3151 (NH), 1633 (C=O), 1522 (C=N), 1203 (C=S), 835 (C-S); HRMS (ESI) m/z (calcd for C19H18N4OS: 350.1201, found 351.1273 [M + H]+; Anal. calcd for C19H18N4OS-0.25H2O: C, 64.29; H, 5.25; N, 15.78; S, 9.03 %. Found: C, 64.10; H, 5.24; N, 15.78; S, 9.22 %.

(E)-2-((6-Methyl-1-(4-nitrobenzyl)-2-oxo-1,2-dihydroquinolin-3-yl) methylene)hydrazinecarbothioamide (9j): 44 % yield; yellow solid; mp 241-243 °C; δH(400 MHz; DMSO-d6): 11.7 (1H, s, N(11)H), 8.83 (1H, s, H9), 8.37 (1H, s, H4), 8.35 (1H, br s, NHH), 8.17-8.16 (2H, m, H3' and H5'), 8.12 (1H, br s, NHH), 7.52 (1H, d, J = 1.3 Hz, H5), 7.47-7.43 (2H, m, H2and H6), 7.37 (1H, dd, J = 1.7 and 8.7 Hz, H7), 7.27 (1H, d, J = 8.7 Hz, H8) ppm; δC(101 MHz, DMSO-d6): 178.1, 160.5, 146.6, 144.7, 136.9, 136.8, 134.8, 132.7, 132.0, 129.3, 127.7, 124.5, 123.8, 120.2, 114.9, 44.7, 20.0 ppm; vmax(neat, cm-1): 3215 (NH), 3150 (NH), 1638 (C=O), 1520 (C=n), 1205 (C=S), 850 (C-S); HRMS (ESI) m/z calcd for C19H17N5O3S: 395.1052, found 396.1135 [M+H]+;Anal.calcdforC19H17N5O3S-0.25H2O:C,57.06; H, 4.41; N, 17.51; S, 8.02 %. Found: C, 56.78; H, 3.98; N, 17.11; S, 7.98 %.

(E)-2-((2-Oxo-1-(prop-2-yn-1-yl)-1,2-dihydroquinolin-3-yl)methy-lene)hydrazinecarbothioamide (9k): 59 % yield; yellow solid; mp 258 °C (Decomposed); δΗ(400 MHz; DMSO-d6): 11.7 (1H, s, N(11)H), 8.83 (1H, s, H9), 8.36 (1H, br s, NHH), 8.32 (1H, s, H4), 8.14 (1H, brs, NHH), 7.72 (1H, m, H7 and H8), 7.61 (1H, d, J = 8.5 Hz, H5), 7.36 (1H, t, J = 7.95 Hz, H6), 5.13 (2H, d, J = 1.9 Hz, H1a), 3.29 (1H, t, J = 2.2 Hz, H2t); δC(101 MHz, DMSO-d6): 178.1, 159.6, 138.2,136.7,136.6,131.4,129.6,124.4,123.0,120.1,115.1,78.6,74.6, 31.4 ppm; vmax(neat, cm-1): 3272 (NH), 3156 (NH), 1645 (C=O), 1532 (C=S), 846 (C-S); HRMS m/z calcd for C14H12N4OS 284.0732, found: 285.0819 [M+H]+; Anal. calcd for C14H12N4OS-0.125H2O: C, 58.67; H, 4.31; N, 19.55; S, 11.19 %. Found: C, 58.69; H, 3.81; N, 19.38; S, 11.15 %.

(E)-2-((6-methoxy-2-oxo-1-(prop-2-ynyl)-1,2-dihydroquinolin-3-yl) methylene)hydrazinecarbothioamide (9l): 56 % yield; yellow solid; mp 232 °C (Decomposed); δH(400 MHz; DMSO-d6): 11.6 (1H, s, N(11)H), 8.70 (1H, s, H9), 8.30 (1H, br s, NHH), 8.32 (1H, s, H4), 8.09 (1H,brs,NHH), 7.46 (1H, d,J = 9.3 Hz, H8), 7.25 (1H, dd,J = 2.9 and 9.2 Hz, H7), 7.15 (1H, d, J = 2.9 Hz, H5), 5.03 (2H, d, J = 2.1 Hz, H1a), 3.75 (3H, s, CH3), 3.18 (1H, t, J = 2.2 Hz,H2t) ppm; δC(101 MHz, DMSO-d6): 178.1, 159.1, 154.6, 136.7, 134.3, 132.8, 124.8, 120.8, 120.1, 116.5, 110.9, 78.8, 74.5, 55.4, 31.4 ppm; vmax(neat, cm-1): 3258 (NH), 3172 (NH), 1635 (C=O), 1203 (C=S), 1521 (C=N), 849 (C-S); HRMS (ESI) m/z calcd for C15H14N4O2S: 298.0888, found 299.0805 [M+H]+; Anal. calcd for C15H14N4O2S: C, 56.94; H, 5.10; N, 17.71; S, 10.14 %. Found: C, 56.52; H, 5.19; N, 17.58; S, 10.33 %.

(E)-2-((6-Methyl-2-oxo-1-(prop-2-yn-1-yl)-1,2-dihydroquinolin-3-yl) methylene)hydrazinecarbothioamide (9m): 60 % yield; yellow solid; mp 244 °C (Decomposed); δH (400 MHz; DMSO-d6): 11.6 (1H, s, N(11)H), 8.75 (1H, s, H9), 8.35 (1H, br s, NHH),8.32 (1H, s, H4), 8.07 (1H, brs, NHH), 7.55 (1H, d, J = 9.3 Hz, H8), 734 (1H, dd, J = 2.9 and 9.2 Hz, H7), 7.23 (1H, d, J = 2.9 Hz, H5), 5.11 (1H, d, J = 2.1 Hz, H1a), 3.25 (1H, t, J = 2.3 Hz,H2t), 2.39 (3H, s, CH3) ppm; δC (101 MHz, DMSO-d6): 178.1, 159.4, 136.8, 136.2, 134.6, 132.6, 132.1, 129.1, 124.3, 120.0, 115.0, 78.8, 74.6, 31.3, 20.1 ppm; vmax(neat, cm-1): 3279 (NH), 3183 (NH), 1627 (C=O), 1522 (C=N), 1206 (C=S), 836 (C-S); HRMS (ESI) m/z calcd for C15H14N4OS: 314.0837, found 315.0927 [M + H]+; Anal. calcd for C15H14N4OS-0.75CH3OH-1H2O: C, 55.57, H; 5.63, N; 16.46, S; 9.42 %. Found; C; 55.32, H; 5.58, N; 16.8, S; 9.98 %.

(E)-2-((1-(2-((7-Chloroquinolin-4-yl)amino)ethyl)-2-oxo-1,2-dihydro quinolin-3-yl)methylene)hydrazinecarbothioamide (9n): 68 yield; yellow solid; mp 235-237 °C; δH(400 MHz; DMSO-d6): 12.6 (1H, s, NH), 8.80 (1H, s, H9), 8.44 (1H, d, J = 5.3 Hz, H2), 8.35 (1H, s, H4), 8.33 (1H, br s, NHh) 8.11 (1H, brs, NHH), 8.06 (1H, d, J = 9.1 Hz, H5'), 7.97 (1H, d, J = 1.9 Hz, H8'), 7.71 (1H, d, J = 7.6 Hz, H5), 7.60 (1H, t, J = 8.6 Hz, H7), 7.57-7.47 (2H, m, H5 and NH), 7.45 (1H, dd, J =1.9 and 9.1 Hz, H6), 7.28 (1H, t, J = 7.4 Hz, H6), 6.72 (1H, d, J = 5.4 Hz, H3'), 4.56 (2H, t, J = 6.6 Hz, CH2), 4.09 (2H, q, J = 6.0, 7.5 and 8.8 Hz, CH2) ppm; dC(101 MHz, DMSO-d6): 178.7, 161.2, 152.5, 150.5, 149.5, 139.7, 137.4, 133.4, 131.9, 130.2, 128.0, 124.9, 124.8, 124.7, 124.2, 123.2, 120.7, 114.9, 99.1, 49.1, 41.1 ppm; vmax(neat, cm-1): 3234 (NH), 3150 (NH), 1633 (C=O), 1515 (C=N), 1204 (C=S), 844 (C-S), 716 (C-Cl); HRMS (ESI) m/z calcd for C22H19ClN6OS: 450.1030, found 451.1099 [M+H]+; Anal. calcd. for C22H19ClN6OS: C, 58.60; H, 4.25; N, 18.64; S, 7.11 %, Found: C, 59.21; H, 4.22; N, 18.55; S, 6.99 %.

(E)-2-((1-(3-((7-Chloroquinolin-4-yl)amino)propyl)-2-oxo-1,2-dihydro-quinolin-3-yl)methylene)hydrazinecarbothioamide (9o): 48 % yield; amorphous yellow solid; mp 240-242 °C; δH(400 MHz; DMSO-d6): 11.6 (1H, s, N(11)H), 8.78 (1H, s, H9), 8.38 (1H, d, J = 5.3 Hz, H2'), 8.34 (1H, s, H4), 8.32 (1H, br s, NHH), 8.25 (1H, d, J = 9.0 Hz, H5'), 8.10 (1H, br s, NHH), 7.79 (1H, d, J = 1.8 Hz, H8,), 7.72 (1H, d, J = 1.0 and 7.7Hz, H8), 7.63 (1H, d, J = 0.7and 8.6 Hz, H5), 7.55 (1H, ddd, J =1.0,7.2 and 9.0 Hz, H6), 7.46 (1H, dd, J =1.8 and 9.0 Hz, H6), 7.391H, s, NH), 7.30 (1H, ddd, J = 0.7,7.2 and 8.6Hz, H7), 6.50 (1H, d, J = 5.4 Hz, H3'), 4.47-4.39 (2H, m, H1'), 3.45-3.41 (2H, m, H3, ), 2.10-2.01 (2H, m, H2) ppm; δC (101 MHz, DMSO-d6): 178.6, 165.3, 160.6, 152.4, 150.5, 139.3, 137.6, 133.9, 130.2, 128.0, 124.9, 124.9, 124.7, 124.6, 124.4, 124.4, 123.1, 120.7, 118.0, 115.1, 99.2,40.8,39.3,26.7 ppm; vmax(neat, cm-1): 3325 (NH), 3234 (NH), 1641 (C=O), 1505 (C=N), 1194 (C=S), 854 (C-S), 712 (C-Cl); HRMS (ESI) m/z calcd for C23H21ClN6OS: 464.1186, found 465.1268 [M+H]+; Anal. calcd for C23H21ClN6OS: C, 59.41; H, 4.55; N, 18.07; S, 6.90 %. Found: C, 59.82; H, 4.44; N, 17.93; S,6.63 %.

(E)-2-((1-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-2-oxo-1,2-dihy-droquinolin-3-yl)methylene)hydrazinecarbothioamide (9p): 45 % yield; yellow solid; mp 240-242 °C; dH(400 MHz; DMSO-d6): 11.7 (1H, s, N(11)H), 8.81 (1H, s, H9), 8.35 (1H, s, H4), 8.32 (1H, br s, NHH), 8.11 (1H, br s, NHH), 8.08 (1H, s, H5 ), 7.73-7.70 (2H, m, H2 and H6 ), 7.38 (1H, ddd, J = 1.2 and 7.3,9.0 Hz, H6), 7.37-7.24 (6H, m, H5,H7,H8,H5,,H4, and H3), 5.55 (2H, s, H4a), 5.51 (2H, s, H1a) ppm; dC(101 MHz, DMSO-d6): 178.1, 160.2, 142.8, 138.9, 136.9, 135.4, 134.7, 131.3, 129.6, 128.7, 128.1, 127.9, 124.5, 123.7, 122.7, 120.1, 115.1, 52.7, 37.7 ppm; vmax(neat, cm-1): 3215 (NH), 3156 (NH), 1634 (C=O), 1524 (C=N), 1567 (N=N), 1203 (C=s), 843 (C-S); HRMS (ESI) m/z calcd for C21H19N7OS: 417.1372, found 418.1455 [M + H]+; Anal. calcd for C21H19N7OS-0.125H2O: C, 60.09; H, 4.62; N, 23.36; S, 7.64 %. Found: C, 60.04; H, 4.52; N,22.99;S, 7.34%.

(E)-2-((1-((1-(4-Nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxo-1, 2-dihydroquinolin-3-yl)methylene)hydrazinecarbothioamide (9q): 55 % yield; yellow solid; mp 258-260 °C; dH(400 MHz; DMSO-d6): 11.7 (1H, s, N(11)H), 8.80 (1H, s, H9), 8.35 (1H, s, H4), 8.33 (1H, br s, NHH), 8.22-8.18 (2H, m, H3„and H5„ ), 8.17 (1H, s, H5 ), 8.11 (1H, s, NHH), 7.74-7.70 (2H, m, H5 and H8), 7.62 (1H, ddd, J = 1.3, 7.2 and 8.9 Hz, H6), 7.52-7.47 (2H, m, H2„ and H6„), 7.31 (1H, ddd, J = 0.5, 7.2 and 8.4 Hz, H7), 5.71 (2H, s, H4a), 5.58 (2H, s, H1a) ppm; dC(101 MHz, DMSO-d6): 178.1, 160.3, 147.3, 143.4, 143.1, 138.9, 136.9,134.8,131.5,129.2,124.6,124.3,123.9,122.9,120.2,51.9ppm; vmax(neat, cm-1): 3361 (NH), 3255 (NH), 1635 (C=O), 1514 (C=N), 1564 (N=N), 1202 (C=S), 847 (C-S); HRMS (ESI) m/z calcd for C21H18N8O3S: 462.1223, found 463.1306 [M+H]+; Anal. calcd for C21H18N8O3S-0.5H2O: C, 53.50; H,4.06; N, 23.77; S, 6.80 %. Found: C, 53.33; H, 3.77; N, 23.95; S, 6.58 %.

(E)-2-((1-((1-(7-Chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxo-1,2-dihydroquinolin-3-yl)methylene)hydrazinecarbothioamide (9r): 46 % yield; amorphous yellow solid; mp 251-253 °C; dH(300 MHz; DMSO-d6): 11.7 (1H, s, N(11)H), 9.10 ( 1H, d, J = 4.6 Hz, H2„ ), 8.84 (1H, s, H9), 8.77 (1H, s, H5 ), 8.38 (1H, s, H4), 8.33 (1H, br s, NHH), 8.26 (1H, d, J = 1.8 Hz, H8'), 8.13 (1H, br s, NHH), 7.97 (1H, d, J = 8.9 Hz, H5 ), 7.85-7.72 (4H, m, H5,H8,H3, and H6 ), 7.67 (1H, ddd, J = 1.3,7.0 and 8.9 Hz, H6), 7.34 (1H, ddd, J = 0.6,7.0,8.6 Hz, H7), 5.76 (2H, s, H4a) ppm; dC(75 MHz, DMSO-d6): 178.1, 160.2, 152.9, 149.3, 143.5, 140.2, 139.0, 136.9, 136.3, 134.8, 131.4, 129.7, 128.9, 128.1, 125.9, 125.4, 124.6, 122.8, 120.2, 117.0, 115.2, 37.5 ppm; vmax(neat, cm-1): 3358 (NH), 3233 (NH), 1638 (C=O), 1517 (C=N), 1568 (N=n), 1516 (c=N), 1205 (C=S), 851 (C-S); HRMS (ESI) m/z calcd for C23H17ClN8OS: 488.0935, found 489.1011 [M+H] + . Anal. calcd for C23H17ClN8OS-0.25H2O: C, 55.98; H, 3.57; N, 22.71; S, 6.50 %. Found: C, 55.81; H, 3.46; N,23.01; S,6.62%.

4.3. Biological Testing and Growth Inhibition Assays

4.3.1. In Vitro Antitrypanosomal and Cytotoxicity Assays

The HeLa cells (Cellonex) were cultured using method described by Oderinlo et al. and Adeyemi et al.30,31 Trypanosoma brucei brucei 427 trypomastigotes were cultured in Iscove s Modified Dulbecco s Medium (IMDM; Lonza) supplemented with 10 % fetal calf serum, HMI-9 supplement,32 hypoxanthine and penicillin/streptomycin at 37 °C ina5%CO2 incubator. Serial dilutions of test compounds were incubated with the parasites in 96-well plates for 24 h and residual parasite viability in the wells determined by adding 20 of 0.54 mM resazurin in phosphate buffered saline (PBS) and incubating for an additional 24 h. Reduction of resazurin to resorufin by viable parasites was assessed by fluorescence readings (excitation 560 nm, emission 590 nm) in a Spectramax M3 plate reader. Fluorescence readings were converted to % parasite viability relative to the average readings obtained from untreated control wells. IC50 values were determined by plotting % viability vs. log[com-pound] and performing non-linear regression using GraphPad Prism (v. 5.02) software.30,31

4.3.2. In Vitro Antiplasmodial Assay

Activity was determined against the 3D7 chloroquine-sensitive strain of P. falciparum. Parasites were maintained in continuous culture using the method of Trager and Jensen33 with modifications. Growth medium consisted of RPMI1640 containing 25 mM HEPES, and further supplemented with 0.5 % (w/v) Albumax II, 22 mM glucose, 0.65 mM hypoxanthine, 0.05 mg mL-1 gentamicin and 2-4 % (v/v) human erythrocytes. Parasites were cultured at 37 °C under an atmosphere of5%CO2,5%O2,90% N2.30,31 Compounds were prepared as 20 mM stock solutions in dimethyl sulfoxide, sonicated for 10 minutes to enhance solubility and stored at -20 °C until use. To assess antimalarial activity, compounds were diluted to a final concentration of 20 in culture medium, added to parasite cultures (2 % parasitaemia, 1 % haematocrit) in 96 well plates and incubated for 48 h at 37 °C under an atmosphere of5%CO2,5%O2,90%N2 Parasite viability was assessed using the parasite lactate dehydrogenase assay described by Makler et al.34 Wells containing uninfected erythro-cytes were used as negative controls (0 % parasite viability) and untreated parasite-infected wells as positive controls (100 % parasite viability). To determine IC50-values, parasite cultures were incubated with 3-fold serial dilutions of test compounds and non-linear regression analysis carried out on dose-response plots of % parasite viability vs. log[compound] using GraphPad Prism (v. 5.02) software.

 

Acknowledgements

We would like to acknowledge the National Research Foundation (NRF) for financial support. The Centre for Chemico- and Biomedicinal Research at Rhodes University is also acknowledged for testing our compounds for their antimalarial activity, using South African Medical Research Council (MRC) funds from National Treasury under its Economic Competitiveness and Support Package. We also gratefully acknowledge Dr Maritjie Stander of Central Analytical Facility (CAF) for mass spectrometry analysis.

 

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Received 26 March 2018
Revised 7 November 2018
Accepted 10 November 2018

 

 

* To whom correspondence should be addressed. E-mail: s.khanye@ru.ac.za

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