Synthesis and antimalarial activity of ( S )-methyl-(7-chloroquinolin-4-ylthio)acetamidoalquilate derivatives

Abstract

The synthesis of five new (S)-methyl-(7-chloroquinolin-4-ylthio)acetamidoalquilate derivatives is carried out under a modified version of the Steglich esterification reaction between different l-amino acid methyl esters and 2-(7-chloroquinolin-4-ylthio)acetic acid. Two of the compounds showed significant inhibition (>50%) of β-hematin formation. The two active structures were tested in vivo as potential antimalarials in mice infected with Plasmodium berghei ANKA, a chloroquine susceptible strain. Compounds 6b and 6e exhibited antimalarial activity comparable to that of chloroquine.

Keywords

β-hematin antimalarial quinoline

Introduction

Malaria is a multifarious tropical disease transmitted by female Anopheles mosquitoes.¹ Five species are encountered: Plasmodium falciparum, vivax, ovale, malariae, and finally, Knowlesi.¹ An increase in malaria cases, more than 2 million from 2016 to 2017 (World Malaria Report),² is due to the lack of proper controls in several countries.³ Vector control is crucial to decrease the transmission of the disease; however, resistance to insecticides and chemotherapeutics has made the task difficult.^2,3 Because of its public health potential, the World Health Organization’s (WHO) top advisory bodies for malaria and immunization have jointly recommended the phased introduction of the vaccine (RTS,S/AS01) in selected areas of sub-Saharan Africa. The only vaccine available, RTS,S, offers partial protection against malaria in young children.⁴ No effective prophylactic vaccine is available.

Monotherapy is no longer used to treat malaria due to the high parasitic resistance exhibited by P. falciparum. Currently, artemisinin-based combination therapy (ACT) is the best available treatment for the malaria caused by P. falciparum.⁵ In ACT, artemisinin and its derivatives are combined with companion drugs such as chloroquine (CQ), amodiaquine (AD), mefloquine (MQ), lumefantrine, sulfadoxine/pyrimethamine, chlorproguanil/dapsone, and piperaquine in an effort to contain the development of parasitic resistance toward rapid-acting artemisinin derivatives.^6–8

These drugs are believed to target the hemozoin formation process in the digestive vacuole (DV) of the malaria parasite P. falciparum.^9–11 Hemozoin (Hz) is an inert crystalline form of ferriprotoporphyrin IX (Fe(III)PPIX), a cytotoxic by-product formed by autoxidation of heme released during parasite digestion of host hemoglobin.¹²

Due to the resistance against quinoline derivatives, there is an urgent need for novel antimalarials with better safety profiles than current medicines.¹³

Several modifications have been made to the side chain of CQ and these have been studied in detail. It has been found that shortening of the chain length or incorporation of an intramolecular hydrogen bonding motif on the side chain of the 4-amino-7-chloroquinoline significantly increases the antimalarial activity.^14–17 Our research group has explored some specific modifications by introducing, acrylate, chalcone, and substituted imidazole moieties on the side chain. Some of the resulting compounds exhibited in vitro activity and significant suppression of parasitemia in the in vivo assay as compared to CQ.^18–22 Motivated by these observations, we synthesized a set of five compounds with specific modifications to CQ that may result in high parasitic activity. The modified compounds were generated through variations of the side chain, that is, position four of quinoline. In the first step, we selected methyl thioglycolate and synthesized various amides through the incorporation of l-amino acids on the carboxyl group. We have found that several of the products exhibited promising antimalarial activity. The results are described herein.

Results and discussion

Scheme 1 shows the general route for the synthesis of the derivatives 6a–e. Detailed data on the synthesis and the physicochemical characteristics of compound 2 have been reported previously.²³ Acid 3 was obtained through alkaline hydrolysis of 2 using a 1 N aqueous solution of NaOH at 60°C for 1 h and the structure was corroborated by the disappearance of the singlet at 3.76 ppm in the ¹H NMR spectrum of 2 and the appearance of a signal at 170.1 ppm in the ¹³C NMR spectrum of 3.

Scheme 1.

Synthesis of (S)-Methyl 2-[2-(7-chloroquinolin-4-ylthio)acetamido]alquilate derivatives 6a–e.

Compounds 6a–e were obtained by a modified version of the Steglich esterification reaction between different l-amino acid methyl esters 5a–e and acid 3 using N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and 4-(dimethylamino)-pyridine (DMAP) in N,N-dimethylformamide (DMF) at room temperature.²⁴

The structures were initially characterized from their IR spectra, which showed the existence of bands in the range of 1728–1750 cm⁻¹ due to the C=O stretch of an ester, and at 1632–1680 cm⁻¹ for the C=O stretch of the amide group.

The structures of 6a–e were also confirmed by ¹H and ¹³C NMR spectroscopy. As a representative example methyl 2-[2-(7-chloroquinolin-4-ylthio)acetamido]propanoate (6a) was selected as a prototype for the study. The ¹H NMR spectrum of 6a displayed one doublet in the aliphatic region at 1.32 ppm, with a J value of 7.9 Hz, corresponding to the CH₃ at position 2″, a singlet at 3.64 ppm attributed to the protons of the ester CH₃, a singlet at 3.84 ppm assigned to CH₂ 2′, a multiplet at 4.53–4.58 ppm attributed to proton 2″, and a doublet at 7.09 ppm (J = 6.9 Hz) assigned to the NH group. The signals for the quinoline ring protons appeared as a doublet at 7.17 ppm (J = 4.7 Hz) attributed to proton 3, a doublet of doublets at 7.52 ppm (J = 2.0 and 8.9 Hz) attributed to proton 6, a doublet at 8.03 ppm (J = 8.9 Hz) corresponding to proton 5, a doublet at 8.08 ppm (J = 2.0 Hz) attributed to proton 8, and a doublet at 8.71 ppm (J = 4.7 Hz) assigned to proton 2.

The ¹³C NMR spectrum of compound 6a showed four signals at 18.1, 35.1, 48.6, and 52.6 ppm assigned to CH₃ (3″), CH₂ (2′), CH (2″), and OCH₃ respectively, and confirmed by DEPT 135°, COSY and HETCOR experiments (supplementary materials). Also, the ¹³C NMR spectrum showed highly deshielded carbonyl carbon resonances at 166.2 ppm (C=O) 1′ and 172.7 ppm (C=O) 1″, while the carbon resonance ranging of the quinoline ring appeared between 116 and 150 ppm. The structures of all the derivatives were determined in a similar fashion.

The l-amino acid methyl esters 5a–e were prepared by adding thionyl chloride to a suspension of amino acids 4a–e in methanol and stirring the reaction mixture at 0°C to room temperature.^25–27

The five derivatives 6a–e were tested in vitro as inhibitors of β-hematin formation, and in vivo for their efficacy in reducing parasite load in a murine model.

In order to evaluate the antimalarial activity, we tested the ability of 6a–e to block heme crystallization, considering that heme can crystallize spontaneously under the acidic and low oxygen conditions found in the vacuole of the parasite.²⁸ More than 50% of inhibition of heme crystallization is considered significant. Compounds 6b and 6e were able to inhibit heme crystallization: 70.07 ± 0.75% and 61.08 ± 0.25%, respectively. The selected compounds that showed potential antimalarial activity in vitro, 6b and 6e, were tested in mice infected with Plasmodium berghei ANKA, a CQ susceptible strain of murine malaria. The antimalarial potential of the compounds was assessed by their ability to reduce parasitemia and increase survival at day four post-infection as compared to the untreated control group.^21,22,29 The results are shown in Table 1. Compounds 6b and 6e, used as monotherapy, prolonged the average survival time of infected mice to 26.04 ± 1.30 and 24.60 ± 2.42 days, respectively, but were not able to reduce or delay the evolution of malaria (1.25 ± 0.47% and 2.08 ± 1.37%). CQ prolonged mouse survival time to 29.20 ± 0.80 days and decreased the development of malaria to 0.32 ± 0.03%.

Table 1.

Percentage of inhibition of β-hematin formation (%IβHF) and the effect of the compounds 6a–e on Plasmodium berghei infected mice (10 mg kg⁻¹).


	R	%IβHF (±SD)	Sd (±SD)	%P (±SD)	Survival^a
6a	CH₃	15.38 ± 0.19	nd	nd
6b	CH(CH₃)₂	70.07 ± 0.75	26.04 ± 1.30*	1.25 ± 0.47^†	5/6
6c	CH₂CH(CH₃)₂	0	nd	nd
6d	CH₂(C₆H₅)	13.58±1.21	nd	nd
6e		61.08±0.25	24.60 ± 2.42*	2.08 ± 1.37^†	3/6
CQ	–	98.52±0.01	29.20 ± 0.80	0.32 ± 0.03	5/6
CiSS	–	–	6.80 ± 0.70	63.20 ± 0.75

SD: standard deviation; Sd: survival days; %P: percentage of parasitemias; CQ: chloroquine; CiSS: Control infected and treated with saline solution.

Number of mice that survived until day 30 post infection/total mice in the group.

p > 0.05 compared to chloroquine; ^†p < 0.001 compared to saline solution and chloroquine (n = 6).

The precise mechanism by which β-hematin inhibitors impede crystal growth is still a matter of debate. All the suggested mechanisms comprise an interaction between the substrate and Fe(III)PPIX.^30,31 De Villiers et al.³² have reported crystal structures of quinidine-heme[QD-Fe(III)PPIX] and quinine-heme [QN-Fe(III)PPIX] complexes, which demonstrate that three significant interactions involving heme binding by these particular drugs involve coordination, hydrogen bonding and π–π stacking.

Conclusion

This work describes a convenient and effective method for the synthesis of (S)-methyl 2-[2-(7-chloroquinolin-4-ylthio)acetamido]alquilate derivatives 6a–e through the reaction of 2-(7-chloroquinolin-4-ylthio)acetic acid (3) with different l-amino acid methyl esters 5a–e using a modified version of the Steglich esterification reaction.

There is a good correlation among inhibition of β-hematin formation, parasitemia reduction, and an increase in the survival of infected mice with products 6b and 6e. Compounds 6b and 6e could be involved in π–π stacking interactions flanked by the porphyrin ring of the hematin structure and the quinoline ring, and bi-directional hydrogen bonding between the amide and propionate groups of the hematin, as has been described for CQ and other aminoquinolines. Although these derivatives were active as inhibitors of β-hematin formation, they were not able to extend the survival rate of infected mice over 30 days. This prolonged survival may be related to pharmacokinetics, pharmacodynamics, and bioavailability and biodegradation of these structures in vivo. Our results are still preliminary and require further analysis, especially with P. falciparum strains, that are CQ susceptible and resistant.

Experimental

The melting points (uncorrected) were recorded using a Thomas Hoover^™ Capillary Melting Point Apparatus. Thin-layer chromatography was carried out on Merck silica F254 0.255 mm plates, and spots were visualized by ultraviolet (UV) fluorescence at 254 nm. The products were purified using open column chromatography on silica gel 60 from Merck (60–120 mesh). The columns were packed wet with chloroform and the compounds were dissolved in dichloromethane and dry-loaded. Chloroform/methanol (9.5:0.5) solvent mixture was used to elute the mixture through the column. Organic products or solvents, purchased from Sigma-Aldrich Group, USA, were used directly or distilled and dried in the usual manner. Amino acids were purchased from Kyowa Hakko Bio Co., Ltd-Tokyo, Japan. Optical rotations were measured with an ATAGO^® Polarimeter model POLAX-2L. NMR spectra were recorded on a JEOL^™ Eclipse 270 MHz instrument for ¹H NMR and at 67.9 MHz for ¹³C NMR using CDCl₃ or DMSO-d6, and are reported in ppm downfield from residual CHCl₃ or DMSO. Elemental analyses were obtained using a Perkin Elmer^™ model 2400 CHN elemental analyses. The results were within ±0.4% of the predicted values. A Shimadzu^™ model 470 spectrophotometer was used to record the IR spectra (as KBr pellets).

Synthesis of Methyl 2-(7-chloroquinolin-4-ylthio)acetate (2)

A mixture of 3.3 mmol of methyl thioglycolate, 15 mmol of triethylamine and 15 mL of dry methanol was stirred at room temperature for 10 min, then 2.6 mmol of 4,7-dichloroquinoline (1) was added. The mixture was stirred at reflux temperature for 24 h and then allowed to cool. The solvent was evaporated under reduced pressure. Subsequently, dichloromethane (40 mL) was added and the organic layer washed with water. Anhydrous sodium sulfate was added to the organic layer, which was filtered and evaporated under reduced pressure. The obtained solid was recrystallized using a mixture of methanol/water (1:1), to give a white solid. Yield: 85%, m.p.: 94–96°C (lit. 98–100°C).^23,33 IR ʋ (cm⁻¹): 1728 (C=O), 1197 and 1168 (C–O). ¹H NMR (270 MHz CDCl₃): δ 3.76 (s, 3H, OCH₃), 3.87 (s, 2H, H-2′), 7.24 (d, 1H, J_3–2 = 4.9 Hz, H-3), 7.50 (dd, 1H, J_6–8 = 2.2 Hz, J_6–5 = 8.3 Hz, H-6), 8.03–8.06 (m, 2H, H-5, H-8), 8.72 (d, 1H, J_2–3 = 4.94 Hz, H-2).

Synthesis of 2-(7-chloroquinolin-4-ylthio)acetic acid (3)

A mixture of compound 2 (3.0 mmol) in aqueous 1 N NaOH 5 mL was heated to 60°C with constant agitation for 1 h. Following completion of the reaction, it was cooled and acidified with 10% HCl until it reached pH = 3. The white solid obtained was filtered and washed with water and diethyl ether. The obtained solid was recrystallized using ethanol. Yield 93%, m.p.: 210°C (decomposition) (lit. 228–229).³³ IR ʋ (cm⁻¹): 1699 (C=O). ¹H NMR (270 MHz DMSO-d₆): δ 4.18 (s, 2H, H-2′), 7.39 (d, 1H, J_3–2 = 4.9 Hz, H-3), 7.68 (dd, 1H, J_6–8 = 2.2 Hz, J_6–5 = 9.1 Hz, H-6), 8.06 (d, 1H, J_8–6 = 1.4 Hz, H-8), 8.11 (d, 1H, J_5–6 = 9.1 Hz, H-5), 8.75 (d, 1H, J_2–3 = 4.94 Hz, H-2). ¹³C NMR (67.9 MHz DMSO-d₆): δ 33.5, 117.5, 124.7, 125.8, 127.8, 128.8, 135.1, 146.8, 147.9, 151.3, 170.1. Anal. calcd for C₁₁H₈ClNO₂S: C, 52.08; H, 3.18; N, 5.52; found: C, 51.97; H, 3.17; N, 5.73.

General procedure for the synthesis of compounds 5a–e

l-amino acids hydrochlorides 4a–e (0.05 mol) in dry methanol 50 mL were converted into the corresponding methyl esters 5a–e in quantitative yields by slowly adding fresh thionyl chloride (0.1 mol) at 0°C and then the mixture was stirred for 4 h. After completion of the reaction, the solvent was evaporated and the product was crystallized from dry diethyl ether.

(S)-Methyl 2-aminopropanoate hydrochloride (5a): white solid, yield 96%, m.p.: 107–109°C (lit. 109–111°C).³⁴ [α](25/D)+ 8.3 (c 1.5, CH₃OH) [lit. [α](20/D)+ 7.0 (c 1.6, CH₃OH)].³⁴

(S)-Methyl 2-amino-3-methylbutanoate hydrochloride (5b): white solid, yield 97%, m.p.: 168–171°C (lit. 171–173°C).³⁴ [α](25/D)+ 17.1 (c 1.5, H₂O) [lit. [α](20/D)+ 15.0 (c 2, H₂O)].³⁴

(S)-Methyl 2-amino-4-methylpentanoate hydrochloride (5c): white solid, yield 94%, m.p.: 149–151°C (lit. 151–153°C).³⁴ [α](25/D)+ 11.7 (c 1.5, H₂O) [lit. [α](22/D)+ 13.0 (c 2, H₂O)].³⁴

(S)-Methyl 2-amino-3-phenylpropanoate hydrochloride (5d): white solid, yield 93%, m.p.: 156–159°C (lit. 158–162°C).³⁴ [α](25/D)+ 38.2 (c 1.5, CH₃CH₂OH) [lit. [α](20/D)+ 32.4 (c 2, CH₃CH₂OH)].³⁴

(S)-Methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride (5e): white solid, yield 95%, m.p.: 221–223°C (lit. 218–220°C).³⁴ [α](25/D)+ 25.0 (c 3.0, CH₃OH) [lit. [α](20/D)+ 32.4 (c 5.0, CH₃OH)].³⁴

General procedure for the synthesis of (S)-Methyl 2-[2-(7-chloroquinolin-4-ylthio)acetamido]alquilate derivatives 6a–e

A solution of 3 (0.6 mmol) in dry DMF (2 mL) at −10°C was treated with EDC (0.8 mmol) and DMAP (0.4 mmol) dissolved in dry DMF (1 mL). The mixture was left shaking at −10°C for 30 min. The respective esterified amino acids 5a–e (0.65 mmol) dissolved in dry DMF (1 mL) were slowly added to the mixture over 30 min. The resulting mixture was left stirring for 12 h at room temperature. Next, water was added and the aqueous fraction was extracted with CH₂Cl₂ (2 × 10 mL). The organic layer was washed with 10% sodium bicarbonate (2 × 8 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The compounds were purified using column chromatography.

(S)-Methyl 2-[2-(7-chloroquinolin-4-ylthio)acetamido]propanoate (6a): Pale yellow solid, yield 32%, m.p.: 138–140°C. IR ʋ (cm⁻¹): 3216 (N-H); 1744 (C=O); 1680 (C=O). ¹H NMR (270 MHz CDCl₃): δ 1.32 (d, 3H, J = 7.9 Hz, CH₃-2″), 3.64 (s, 3H, OCH₃), 3.84 (s, 2H, H-2′), 4.53–4.58 (m, 1H, H-2″), 7.09 (d, 1H, J = 6.9 Hz, N-H), 7.17 (d, 1H, J_3–2 = 4.7 Hz, H-3), 7.52 (dd, 1H, J_6–8 = 2.0 Hz, J_6–5 = 8.9 Hz, H-6), 8.03 (d, 1H, J_5–6 = 8.9 Hz, H-5), 8.08 (d, 1H, J_8–6 = 2.0 Hz, H-8), 8.71 (d, 1H, J_2–3 = 4.7 Hz, H-2). ¹³C NMR (67.9 MHz CDCl₃): δ 18.1, 35.1, 48.6, 52.6, 116.9, 124.7, 127.9, 129.0, 136.2, 145.4, 147.9, 150.4, 166.2, 172.7. [α](25/D) + 60.3 (c 0.5, CHCl₃). Anal. calcd for C₁₅H₁₅ClN₂O₃S: C, 53.17; H, 4.46; N, 8.27; found: C, 53.19; H, 4.51; N, 8.41.

(S)-Methyl 2-[2-(7-chloroquinolin-4-ylthio)acetamido]-3-methylbutanoate (6b): Orange solid, yield 43%, m.p.: 98–100°C. IR ʋ (cm⁻¹): 3296 (N-H); 1737 (C=O); 1651 (C=O). ¹H NMR (270 MHz CDCl₃): δ 0.69 (d, 6H, J = 16.1 Hz, CH₃-3″), 2.01–2.13 (m, 1H, H-3″), 3.63 (s, 3H, OCH₃), 3.88 (s, 2H, H-2′), 4.47–4.52 (m, 1H, H-2″), 7.01 (d, 1H, J = 8.4 Hz, N-H), 7.19 (d, 1H, J_3–2 = 4.7 Hz, H-3), 7.53 (dd, 1H, J_6–8 = 1.9 Hz, J_6–5 = 8.9 Hz, H-6), 8.04–8.07 (m, 2H, H-5, H-8), 8.70 (d, 1H, J_2–3 = 4.7 Hz, H-2). ¹³C NMR (67.9 MHz CDCl₃): δ 17.6, 31.1, 35.1, 52.2, 57.6, 116.9, 124.7, 127.9, 129.1, 136.2, 145.4, 147.9, 150.3, 166.5, 171.7. [α](25/D)+ 52.1 (c 1.5, CHCl₃). Anal. calcd for C₁₇H₁₉ClN₂O₃S: C, 55.66; H, 5.22; N, 7.64; found: C, 55.60; H, 5.27; N, 7.93.

(S)-Methyl 2-[2-(7-chloroquinolin-4-ylthio)acetamido]-4-methylpentanoate (6c): Orange solid, yield 27%, m.p.: 116–118°C. IR ʋ (cm⁻¹): 3216 (N-H); 1744 (C=O); 1680 (C=O). ¹H NMR (270 MHz CDCl₃): δ 0.74 (d, 6H, J = 11.1 Hz, CH₃-4″), 1.23–1.46 (m, 1H, H-4″), 1.50–1.60 (m, 2H, H-3″), 3.63 (s, 3H, OCH₃), 3.86 (s, 2H, H-2′), 4.57–4.60 (m, 1H, H-2″), 6.90 (d, 1H, J = 7.9 Hz, N-H), 7.17 (d, 1H, J_3–2 = 5.7 Hz, H-3), 7.52 (dd, 1H, J_6–8 = 2.2 Hz, J_6–5 = 8.9 Hz, H-6), 8.03 (d, 1H, J_5–6 = 8.9 Hz, H-5), 8.07 (s, 1H, H-8), 8.70 (d, 1H, J_2–3 = 5.7 Hz, H-2). ¹³C NMR (67.9 MHz CDCl₃): δ 22.7, 24.8, 35.1, 41.3, 51.2, 52.4, 116.9, 124.7, 127.9, 129.1, 136.2, 145.3, 147.9, 150.3, 166.4, 172.7. [α](25/D) + 47.0 (c 1.0 CHCl₃). Anal. calcd for C₁₈H₂₁ClN₂O₃S: C, 56.76; H, 5.56; N, 7.35; found: C, 56.81; H, 5.60; N, 7.59.

(S)-Methyl 2-[2-(7-chloroquinolin-4-ylthio)acetamido]-3-phenylpropanoate (6d): Brown solid, yield 31%, m.p.: 146–148°C. IR ʋ (cm⁻¹): 3296 (N-H); 1750 (C=O); 1661 (C=O). ¹H NMR (270 MHz CDCl₃): δ 2.86–3.04 (m, 2H, H-3″), 3.68 (s, 3H, OCH₃), 3.79 (s, 2H, H-2′), 4.78–4.83 (m, 1H, H-2″), 6.79–6.93 (m, 6H, N-H, ArH), 7.00 (d, 1H, J_3–2 = 4.5 Hz, H-3), 7.53 (dd, 1H, J_6–8 = 2.2 Hz, J_6–5 = 9.0 Hz, H-6), 7.96 (d, 1H, J_5–6 = 8.9 Hz, H-5), 8.10 (d, 1H, J_8–6 = 2.2 Hz, H-8), 8.62 (d, 1H, J_2–3 = 4.7 Hz, H-2). ¹³C NMR (67.9 MHz CDCl₃): δ 34.7, 37.6, 52.5, 53.4, 116.5, 124.7, 127.2, 127.8, 128.5, 128.9, 135.2, 136.2, 145.5, 147.7, 150.3, 166.3, 171.4. [α](25/D) + 18.1 (c 1.0, CHCl₃). Anal. calcd for C₂₁H₁₉ClN₂O₃S: C, 60.79; H, 4.62; N, 6.75; found: C, 60.73; H, 4.67; N, 6.90.

(S)-Methyl 2-[2-(7-chloroquinolin-4-ylthio)acetamido]-3-(1H-indol-3-yl)propanoate (6e): Beige solid, yield 27%, m.p.: 186–188°C. IR ʋ (cm⁻¹): 3312 (N-H); 1728 (C=O); 1632 (C=O). ¹H NMR (270 MHz DMSO-d₆): δ 3.13–3.19 (m, 2H, H-3″), 3.59 (s, 3H, OCH₃), 4.00 (s, 2H, H-2′), 4.57–4.63 (m, 1H, H-2″), 6.95 (d, 1H, J = 7.6 Hz, N-H), 7.07 (t, 1H, J_4‴6‴ = 7.6 Hz, H-5‴), 7.18 (d, 1H, J_3–2 = 4.9 Hz, H-3), 7.33 (t, 1H, J_5‴7‴ = 7.6 Hz, H-6‴), 7.48 (d, 1H, J_4‴5‴ = 7.7 Hz, H-4‴), 7.56 (d, 1H, J_7‴6‴ = 7.7 Hz, H-6‴), 7.66 (dd, 1H, J_6–8 = 2.21 Hz, J_6–5 = 8.90 Hz, H-6), 8.04–8.09 (m, 2H, H-5, H-8), 8.60 (d, 1H, J_2–3 = 4.9 Hz, H-2), 8.86 (d, 1H, J = 8.6 Hz, H-2‴), 10.91 (s, 1H, NH-1‴). ¹³C NMR (67.9 MHz DMSO-d): δ 27.7, 34.5, 52.5, 54.1, 109.8, 112.0, 117.7, 118.5, 119.1, 121.6, 124.3, 124.7, 125.8, 127.7, 127.8, 128.8, 134.9, 136.8, 147.1, 147.9, 151.2, 167.4, 172.5. [α](25/D)+ 13.7 (c 0.5, CH₃OH). Anal. calcd for C₂₃H₂₀ClN₃O₃S: C, 60.86; H, 4.44; N, 9.26; found: C, 60.95; H, 4.50; N, 9.49

Inhibition of β-hematin formation

The assay was performed according to previously reported protocols.^21,22,35

Parasite, experimental host, strain maintenance, and 4-day suppressive test

Male Balb-C mice, weight 18–22 g, were maintained on a commercial pellet diet at libitum and under conditions approved by the Ethics Committee of the Institute of Immunology, Faculty of Medicine, Central University of Venezuela. A rodent malaria ANKA strain of P. berghei, parasite, was used to infect the animals. The parasitemia were scrutinized by microscopic examination of Giemsa stained smears.^21,22

Two hours after infection, the compounds that inhibited β-hematin formation in vitro were used administered ip for 4 days (10 mg kg⁻¹). At day 4, the parasite load was assessed by examining Giemsa stained smears. CQ (10 mg kg⁻¹) was used as a positive control.²⁹ One-way analysis of variance (ANOVA) and T tests for specific group comparisons were used for data analysis. The program used was Graph Pad Prism 3.02.³⁶

Supplemental Material

Suplementary_data – Supplemental material for Synthesis and antimalarial activity of (S)-methyl-(7-chloroquinolin-4-ylthio)acetamidoalquilate derivatives

Supplemental material, Suplementary_data for Synthesis and antimalarial activity of (S)-methyl-(7-chloroquinolin-4-ylthio)acetamidoalquilate derivatives by Custodiana Colmenarez, María Acosta, Miguel Rodríguez and Jaime Charris in Journal of Chemical Research

Footnotes

Acknowledgements

The authors thank Dr Juan B. Sanctis for his helpful comments.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Instituto de Investigaciones Farmacéuticas (IIF) (grant IIF.01-2014) and Consejo de Desarrollo Científico y Humanistico-Universidad Central de Venezuela (CDCH-UCV) (grant PG. 06-8627-2013/2).

ORCID iD

Jaime Charris

Supplemental material

Supplemental material for this article is available online.

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