Discovery of highly selective 7-chloroquinoline-thiohydantoins with potent antimalarial activity

doi:10.1016/j.ejmech.2014.07.048

European Journal of Medicinal Chemistry

Volume 84, 12 September 2014, Pages 425-432

https://doi.org/10.1016/j.ejmech.2014.07.048 Get rights and content

Highlights

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Synthesis and antimalarial evaluation of 7-chloroquinoline-thiohydantoins.
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Most potent scaffold exhibited IC₅₀ of 39.8 nM with high selectivity.
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Studies of β-hematin formation further confirmed their mechanism of action.

Abstract

A series of C-3 thiourea functionalized β-lactams, β-lactam-7-chloroquinoline conjugates and 7-chloroquinoline-thiohydantoin derivatives were prepared with the aim of probing antimalarial structure–activity relationships. 7-Chlorquinoline-thiohydantoin derivatives were found to be potent inhibitors of cultured Plasmodium falciparum, with the most potent and non-cytotoxic compound exhibiting an IC₅₀ of 39.8 nM. Studies of β-hematin formation suggested that inhibition of haemozoin formation could be primary mechanism of action, with IC₅₀ values comparable to those of chloroquine. Evaluation of cytotoxicity against HeLa cells demonstrated high selective indices.

Graphical abstract

Synthesis, antimalarial and cytotoxic evaluation of C-3 functionalized β-lactams, β-lactam-7-chloroquinoline conjugates and 7-chloroquinoline-thiohydantoin derivatives.

Introduction

Malaria is considered to be the most prevalent human parasitic disease and remains as one of the world's greatest health challenges. About 2.2 billion people live in malaria endemic areas, and the World Health Organization (WHO) estimated that 207 million cases and 627,000 deaths occurred in 2012, mostly in young children [1]. This disease is caused by mosquito-borne protozoa of the genus Plasmodium. Among the Plasmodial species, Plasmodium falciparum is the most problematic, due to its high prevalence, virulence and drug resistance and is responsible for most malaria-related deaths [2]. Antimalarial drugs with a quinoline scaffold were extensively utilized for the treatment of malaria [3]. However, the emergence of resistance to chloroquine (CQ) and other drugs has limited their utility and are no longer administered in most countries [4]. CQ resistance is mainly attributed to mutations in the P. falciparum chloroquine resistance transporter gene (PfCRT), with the mutant protein mediating the export of the drug out of digestive vacuole of the parasite and hence away from its site of action [5]. The newer drugs of choice for the treatment of infection with P. falciparum are now artemisinin-based combination therapies (ACTs). ACTs contain derivatives of the natural endoperoxide compound artemisinin (artemether, artesunate and dihydroartemisinin), which are potent and fast acting antimalarials. These are combined with longer acting partner drugs that kill parasites that are not cleared by artemisinins and help to prevent selection of drug resistant parasites [6]. However, recent reports of delayed parasite clearance after treatment with ACTs in southeast Asia are disconcerting, and have provided the impetus for the discovery of new antimalarials to feed the preclinical pipeline [7]. Among existing pharmacophore templates, chloroquinoline class of therapeutics remain successful for combating malaria even after several decades of drug development efforts due to its excellent clinical efficacy, ease of administration, low toxicity, and low cost synthesis [8].

Historically, a constrained β-lactam ring is a feature of an important class of antibiotics, after the discovery of naturally occurring penicillins and cephalosporins [9]. A broad spectrum of biological properties has also been associated with β-lactams, including inhibition of HIV-1 protease [10], inhibition of cholesterol absorption [11], antiviral [12], antitumor [13] and antimalarial activity [14]. Recent studies have also identified the β-lactam moiety as a versatile synthon for the preparation of diversely functionalized heterocycles [15], [16].

The introduction of urea, oxalamide, and thiourea functionalities in 4-aminoquinolines has been shown to enhance antimalarial activity, which may be attributed to their ability to form hydrogen bonds. In addition to their inhibition of β-hematin formation, these derivatives have also been identified as potent antimalarials targeting the dihydrofolate reductase (DHFR) enzyme, a well defined and widely exploited target in antimalarial chemotherapy [17], [18]. Recent contributions from our group have shown the potential of β-lactam-4-aminoquinoline conjugates as antimalarial agents. A diverse range of linkers viz. amide [19] and non-ionizable covalent bonds [19], urea [20] and oxalamide [20] functionalities have been introduced in such hybrids along with well modulated alkyl chain length between the two amino functionality at the C-4 position of the quinoline ring. From these studies, the most potent and non-cytotoxic conjugate, with an optimum combination of N-cyclohexyl substituent at N-1, alkyl chain length (n = 6) and oxalamide functionality exhibited an IC₅₀ of 39.8 nM. Encouraged by these results, we describe the synthesis and antimalarial evaluation of thiourea tethered 7-chloroquinoline-β-lactam conjugates and 7-chloroquinoline-thiohydantoin analogs, based on the established antimalarial potential of the thiohydantoin structural motif [21].

Section snippets

Synthetic chemistry

The treatment of precursor 3-isothiocyanato-2-azetidinones 1, synthesized via Staudinger reaction of 3-azido-β-lactam with triphenylphosphine and carbon disulfide, with primary aliphatic/aromatic amines resulted in the isolation of corresponding thioureas 2. Sodium methoxide promoted tandem intramolecular amidolysis-β-elimination led to the formation of corresponding thiohydantoins 3 in good to excellent yields (Scheme 1).

For the synthesis of thiourea-tethered 7-chloroquinoline-β-lactam

Experimental section

Melting points were determined by open capillary using a Veego Precision Digital Melting Point apparatus (MP-D) and are uncorrected. IR spectra were recorded on a Shimadzu D-8001 spectrophotometer. ¹H NMR spectra were recorded in deuterochloroform and dimethylsulfoxide-d₆ with a Jeol 300 (300 MHz) spectrometer using TMS as an internal standard. Chemical shift values are expressed as parts per million downfield from TMS and J values are in hertz. Splitting patterns are indicated as s: singlet,

Acknowledgments

V.M. gratefully acknowledge the Senior Research Fellowship granted under CSIR Open Scheme 09/254(0244)/2012-EMR-I.

References (28)

D.A. Fidock et al.
Mol. Cell.
(2000)
L.H. Miller et al.
Cell
(2011)
V.V. Kouznetsov et al.
Eur. J. Med. Chem.
(2009)
T. Sperka et al.
Bioorg. Med. Chem. Lett.
(2005)
S. Vandekerckhove et al.
Bioorg. Med. Chem.
(2013)
G. Veinberg et al.
Bioorg. Med. Chem. Lett.
(2004)
M. Nivsarkar et al.
Bioorg. Med. Chem. Lett.
(2005)
G.S. Singh et al.
Tetrahedron
(2011)
V. Mehra et al.
Tetrahedron Lett.
(2014)
N. Sunduru et al.
Bioorg. Med. Chem. Lett.
(2009)

P. Singh et al.

Eur. J. Med. Chem.

(2014)

B. Zhong et al.

Tetrahedron Lett.

(2006)

K.K. Ncokazi et al.

Anal. Biochem.

(2005)

WHO

World Malaria Report 2012

(2012)

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The currently available treatment options for leishmaniasis are associated with high costs, severe side effects, and high toxicity. In previous studies, thiohydantoins demonstrated some pharmacological activities and were shown to be potential hit compounds with antileishmanial properties.
The present study further explored the antileishmanial effect of acetyl-thiohydantoins against Leishmania amazonensis and determined the main processes involved in parasite death. We observed that compared to thiohydantoin nuclei, acetyl-thiohydantoin treatment inhibited the proliferation of promastigotes. This treatment caused alterations in cell cycle progression and parasite size and caused morphological and ultrastructural changes. We then investigated the mechanisms involved in the death of the protozoan; there was an increase in ROS production, phosphatidylserine exposure, and plasma membrane permeabilization and a loss of mitochondrial membrane potential, resulting in an accumulation of lipid bodies and the formation of autophagic vacuoles on these parasites and confirming an apoptosis-like process. In intracellular amastigotes, selected acetyl-thiohydantoins reduced the percentage of infected macrophages and the number of amastigotes/macrophages by increasing ROS production and reducing TNF-α levels. Moreover, thiohydantoins did not induce cytotoxicity in murine macrophages (J774A.1), human monocytes (THP-1), or sheep erythrocytes. In silico and in vitro analyses showed that acetyl-thiohydantoins exerted in vitro antileishmanial effects on L. amazonensis promastigotes in apoptosis-like and amastigote forms by inducing ROS production and reducing TNF-α levels, indicating that they are good candidates for drug discovery studies in leishmaniasis treatment. Additionally, we carried out molecular docking analyses of acetyl-thiohydantoins on two important targets of Leishmania amazonensis: arginase and TNF-alpha converting enzyme. The results suggested that the acetyl groups in the N1-position of the thiohydantoin ring and the ring itself could be pharmacophoric groups due to their affinity for binding amino acid residues at the active site of both enzymes via hydrogen bond interactions. These results demonstrate that thiohydantoins are promising hit compounds that could be used as antileishmanial agents.
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In asymmetric catalysis, optically pure thiohydantoins and hydantoins have been broadly used as metal ligands and chiral auxiliaries in asymmetric catalysis [3]. On the other hand, CC triple bond is one of the most essential functionalities with a rich reactivity profile in the field of organic chemistry and other versatile fields [4]. In view of these properties, synthesis and functionalization of heterocyclic skeletons possessing both alkyne group and thiohydantoin structural units may benefit the research arenas of drug discovery and chemical science.
Herein, A novel strategy for Iron(II)-catalyzed alkynylation of thiohydantoins with terminal alkyne has been firstly reported. Optimization study was carried out through various catalysts, oxidants and solvents. The merit of this strategy is illustrated by the breadth of functional groups tolerated in the transformation. This study offers a unified method to access several alkynylated thiohydantoins in moderate to higher yield via C(sp³)-C(sp) bond formation.
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An unusual diverse coordination of silver(I) with N-allylthiohydantoin ligand in the presence of benzene- and p-toluenesulfonate anions
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Heterocyclic compounds containing 2-thioxoimidazolidin-4-ones (namely 2-thiohydantoin) fragment possess valuable pharmaceutical properties such as anticarcinogenic, antimutagenic, antimicrobial, anticonvulsant, etc. [1–7].
Crystalline silver(I) coordination compounds [Ag₂(HL)₄(C₆H₅SO₃)₂]·0.5C₃H₇OH (1) and [Ag₂(HL)(L)(CH₃C₆H₄SO₃)] (2) (HL = 3-(prop-2-en-1-yl)-2-thioxoimidazolidin-4-one) have been obtained using silver(I) salts and the organic ligand HL. Three independent Ag(I) atoms in crystal 1 adopt exclusively different coordination environment: tetragonal pyramidal, seesaw and distorted tetrahedral. In crystal 2 metal ions coordination polyhedra are characterized by seesaw and distorted tetrahedral arrangements. Thiohydantoin molecules in both structures are attached to Ag(I) only through thiohydantoin S-atom, while its anionic form in 2 plays a role of N,S-linker. C₆H₅SO₃⁻ anions in 1 are bound to the Ag(I) ions in a bridging mode, connecting silver ions into serpentine-like {Ag₄(C₆H₅SO₃)₄}_n chains, within which silver ions are additionally bind with µ₂-S atoms of HL. Simultaneous coordination of HL and L⁻ moieties in polymeric chains of 2 allow the formation of Ag….Ag metallophilic interactions with the distance range of 2.99–3.13 Å.
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Thiohydantoin moiety is one of the most important scaffolds for pharmaceutical research [1], because thiohydantoins have been used as biologically active compounds [1,2] and intermediate compounds for the synthesis of biologically important compounds [3]. Thiohydantoin derivatives are known to show a wide range of pharmacological properties, such as antimicrobial [2a,4], antimalarial [5] and antiproliferative agents [6], NADPH oxidase (NOX) inhibitor [7], topoisomerase I inhibitor [8] and androgen receptor antagonist [9]. The pyrrolidine ring is also one of the most studied structures in pharmaceutical research as pharmacophore group [10].
A novel bicyclic thiohydantoin fused to pyrrolidine compound, methyl 2-(4-chlorophenyl)-7a-((4-chlorophenyl)carbamothioyl)-1-oxo-5,5-diphenyl-3-thioxo-hexahydro-1H-pyrrolo[1,2-e]imidazole-6-carboxylate, was synthesized by the cyclization reaction of dimethyl 5,5-diphenylpyrrolidine-2,4-dicarboxylate and 4-chlorophenyl isothiocyanate in the presence of 4-(dimethylamino)pyridine to form methyl 2-(4-chlorophenyl)-1-oxo-5,5-diphenyl-3-thioxo-hexahydro-1H-pyrrolo[1,2-e]imidazole-6-carboxylate with concomitant addition reaction of the 4-chlorophenyl isothiocyanate in 79% yield. The structural characterization was performed by NMR, FT-IR, MS and HRMS techniques, and the stereochemistry of the compound was determined by single crystal X-ray diffraction study. In addition, the molecular structure and ¹H and ¹³C NMR chemical shifts of the compound were obtained with the density functional theory and Hartree-Fock calculations. Acid dissociation constants of the compound were determined using potentiometric titration method in 25% (v/v) dimethyl sulfoxide-water hydroorganic solvent at 25 ± 0.1 °C, at an ionic background of 0.1 mol/L of NaCl using the HYPERQUAD computer program. Four acid dissociation constants were obtained for the compound, and we suggest that these acid dissociation constants are related to the NH, for two groups of enthiols and enol groups. Antimicrobial activity study was performed against S. aureus, B. subtilis, A. hydrophila, E. coli and A. baumannii as bacterial standard strains, and against M. tuberculosis H37Rv as mycobacterial strain. The compound exhibited antibacterial activity in the range of 31.25–62.5 μg/mL, and antimycobacterial activity with a MIC value of 40 μg/mL against the indicated strains.

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Preliminary communicationDiscovery of highly selective 7-chloroquinoline-thiohydantoins with potent antimalarial activity

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Synthetic chemistry

Experimental section

Acknowledgments

Mol. Cell.

Cell

Eur. J. Med. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Tetrahedron

Tetrahedron Lett.

Bioorg. Med. Chem. Lett.

Eur. J. Med. Chem.

Tetrahedron Lett.

Anal. Biochem.

World Malaria Report 2012

Preliminary communication
Discovery of highly selective 7-chloroquinoline-thiohydantoins with potent antimalarial activity