Bioactive glycosides: insights into antimalarial advances

Abstract

Glycochemistry has broadened the scope of drug discovery by offering new avenues for developing potent and safe medicines. Glycosylation improves physicochemical and pharmacokinetic properties of bioactive compounds, inspiring further exploration of glycosylated drug candidates. This review delves into the significance of carbohydrate-based bioactive compounds with promising antiplasmodial and antimalarial activity for the development of effective antimalarials.

Graphical Abstract

antimalarial, carbohydrate, glycosylation

1. Introduction

The worrying rate of death from malarial infections worldwide has amplified awareness and effort on developing novel and potent antimalarials. With over 300 million new cases yearly and 608,000 deaths in 2022 alone,¹ malaria, transmitted via Plasmodium-infected female Anopheles mosquitoes, is categorized as one of the deadliest infectious diseases.^2,3 malaria, transmitted via Plasmodium-infected female Anopheles mosquitoes, is categorized as one of the deadliest infectious diseases.^2,3 The most lethal Plasmodium parasite, Plasmodium falciparum, accounts for ∼90% of malaria global fatalities.⁴ As highlighted by the World Health Organization, developing novel and effective malaria diagnosis, therapeutics, case management, prevention, elimination, and surveillance strategies are urgently needed.⁵ Current approaches to curb the spread of malaria are focused on rapid diagnostic tests and vector controls through the use of insecticides, insecticide-treated mosquito nets, as well as the RTS,S/AS01 (Mosquirix) and R21/Matrix-M malaria vaccines.^1,6 Concurrently, the rapid spread of Plasmodium resistance compromises the effectiveness of present antimalarial medications, including the widely prescribed artemisinin-based combination therapies.^1,7,8 Therefore, a current direction in antimalarial research is the exploration of alternative medicine from both natural and synthetic resources.^2,9–12

Discovering effective therapy with acceptable dosage and cost has been one of the most significant challenges in drug development. The exploration of hybrid compounds including glycosides has resulted in promising bioactive compounds in treating various conditions, including cancer,^13,14 diabetes, diseases related to bacterial,^15–17 viral, and fungal infections,^18,19 as well as inflammation.^20,21 Carbohydrates are vital for many cellular processes, including biomolecular recognition involving receptors, enzymes, and hormones.^22–24 Glycoproteins and glycolipids that are present on the cell surface in various forms are major mediators of intermolecular interactions.^21,25–27 Hence, the incorporation of glycosides in the synthesis of promising derivatives represent a fascinating intersection of chemistry and biology in drug design.

Developing sugar-conjugated compounds through glycosylation has gained significant attention in drug discovery, mainly due to the unique properties imparted by sugar moieties.²⁸ Glycosylation, the process of attaching a sugar moiety at its anomeric position to another molecule, can improve the absorption and distribution of compounds for enhanced bioavailability and bioactivity. These enhancements are attributable to the higher aqueous solubility and metabolic stability due to the presence of hydrophilic sugar moieties.^24,29 Nevertheless, glycosides are generally not stable when administrated orally, as the presence of gastric acid and intestinal glycosidases could hydrolyze the glycosidic bonds, leading to the breakdown of glycosides into their constituent sugars and aglycones.^30–32

However, research on utilizing carbohydrates for developing more effective antimalarials remains relatively limited. Among the new chemical entities (NCEs) made available worldwide within the year 2000 to 2021, only 54 drugs are carbohydrate-based and have been approved for therapeutic applications.²⁰ This review discusses the exploration of glycosides in the preliminary and advanced stages of drug discovery, and presents an overview of glycosylated derivatives with promising antiplasmodial and antimalarial potential as innovative future therapies.

2. Glycosylated compounds in antimalarial drug development

From the mid-19th century to the 1940s, quinine became the standard medication for malaria, before the development of chloroquine (CQ) in the 1940s, followed later by quinoline and artemisinin derivatives.^33–36 However, poor bioavailability and parasite resistance have been the primary challenges with these drugs.^1,37,38 Hence, antimalarial compounds should be designed to not only address drug resistance and toxicity, but should also elicit immediate action upon administration and be curative with a single dose.³⁹

Previously, the authors have explored the antimalarial potential of several natural products, including those from plants (steroids from Diplazium esculentum,⁴⁰ engeletin from Artocarpus scortechinii,⁴¹ cinnamic acid derivatives from Gleichenia truncata,⁴²Portulaca oleracea L⁴³) and microbes (actinomycetes from Malaysian forest soil,⁴⁴ endophytic actinomycetes from timber trees^45,46). This was extended to synthesizing derivatives of natural compounds such as chalcones,⁴⁷ quercetin,⁴⁸ aromatic turmerone,⁴⁹ and curcumin.^9,50 However, the antiplasmodial activities exhibited by natural compounds are generally suboptimal. Therefore, we are currently exploring the therapeutic potential of conjugating carbohydrate moieties to these compounds to improve their bioactivity.

Glycosides have shown potent antimalarial efficacy, with many exhibiting better effectiveness than their aglycones (Fig. 1 and Table 1). Hybrid compounds are expected to not only overcome the emergence of drug resistance by circumventing pathways involved in the resistance mechanism, but the conjugated pharmacophoric entities are generally also more metabolically stable and bioavailable inside the human body.^74–77 Previous studies on adjunct antimalarial therapies based on glycosides have elucidated their potential in managing malaria.^52,78 Such conjugation holds promise similar to those of carbohydrate-based NCEs and is expected to yield more potent antimalarial compounds.⁷⁹

Fig. 1.

Carbohydrate-based compounds with proven antiplasmodial and antimalarial bioactivity.

Table 1.

Biological activities of glycosylated compounds in Fig. 1.

No	Compounds and sources	Bioactivity				Ref.
1	C-Glycosylated derivatives isolated from Streptomyces sp.	Antiplasmodium Potent IC50 against P. falciparum K1 strain				51
		1a = 0.053 μg/mL		1c = 0.142 μg/mL
		1b = 0.173 μg/mL		1d = 2.93 μg/mL
2	Glycosides extracted from Solanaceae plants (Solanumtuberosum L.)	Antimalarial 6-OH of sugar moiety is crucial for antimalarial activity. ED50 = 4.49 mg/kg Active over 4 d of observation (Dose: 7.5 mg/kg) Parasitemia = 6.77% ± 2.13%		Parasite suppression = 71.38%		52,53
3	Glycosides extracted from Solanaceae plants (Solanumtuberosum L.)	Antimalarial Active against Plasmodium yoelii over 4 d with (Dose: 7.5 mg/kg)				52,53
		Parasitemia = 10.06% ± 2.15%		Parasite suppression: 57.47%
4	Steroidal glucopyranoside extracted from Solanum nudum	Antiplasmodium Inhibition of β-hematin (hemozoin) formation:				54
		4		33.4% (4 mM concentration)	27.1% (0.4 mM concentration)
		CQ		79.5% (5 mM concentration)	25.9% (0.5 mM concentration)
5	Steroidal pregnane Marine Octocoral Muricea austera	Antiplasmodium Potent IC50 against P. falciparum CQ-resistant W2 strain.				55
		5 = 16 μM		Deacetylated 5 = 32 μM
6	Jacaranone-derived glucosidic esters from Jacaranda glabra	Antiplasmodium Potent IC50 against the P. falciparum K1 strain and low toxicity against L-6 cells, with the presence of glycosidic ester groups enhanced the activity.				56
		6		K1 = 1.02 ± 0.29 μM	L-6 = 84.8 ± 4.8 μM
		Phenylacetic acid		K1 = >5 μM	L-6 = >90 μM
		CQ		K1 = 0.06 μM	L-6 = n/a
7	Hexadecyl disaccharide isolated from the root bark of Matayba guianensis	Antiplasmodium Potent IC50 against the P. falciparum CQ-resistant FcB1/Colombia strain Aglycon C16H33OH showed a loss of antimalarial activity.				52,57
		7a = 8.0 μM	7b = 4.7 μM	7c = 11.7 μM	7d = 3.4 μM
8	Ferrocenyl CQ conjugated with sugar	Antiplasmodium Potent IC50 against P. falciparum CQ-sensitive D10 and CQ-resistant Dd2 and K1 strains with consistently higher in vitro activity than CQ.				28,58
		8		D10 = 72.8 nM	Dd2 = 104 nM
		No-sugar ferroquine		D10 = 138 nM	Dd2 = 300 nM
		CQ		D10 = 38.3 nM	Dd2 = 388 nM
9	Norbergenin derivative from Diospyros sanza-minika (Ebenaceae) stem bark	Antiplasmodium Potent IC50 against the P. falciparum CQ-resistant K1 strain and better CC50 cytotoxicity than CQ against MRC-5 cells				52,59
		IC50		9 = 0.6 μg/mL	CQ = 0.8 g/mL
		CC50		9 = 24.7 μg/mL	CQ = >64 μg/mL
10	C-Glycosides with sulfonamidyl and ureidyl moieties	Antiplasmodium Potent IC50 against P. falciparum CQ-sensitive 3D7 and CQ-resistant K1 strains:				60,61
		10a		3D7 = 1.14 µM	K1 = 2.17 µM
		10b		3D7 = 0.55 μM	K1 = 0.42 μM
		10c		3D7 = 0.56 μM	K1 = 1.58 μM
		CQ		3D7 = 0.011 μM	K1 = 1.16 μM
		Phenyl sulfonamidyl		3D7 = >20 μM	K1 = >20 μM
		Diaryl ureidyl		3D7 = >20 μM	K1 = >20 μM
		Diaryl thioureidyl		3D7 = >20 μM	K1 = 18.01 μM
		Inhibition of heme polymerization:		10a = 6.39% 10b = 72.13%	10c = 43.49% 10d = 64.7%
11	Monodesmosic saponin glycyrrhizin (GLR) extracted from the Glycyrrhiza glabra (licorice) plant	Antimalarial Active against P. falciparum based on its identified 3 main mechanisms of action: i) disorganization of membrane lipid rafts ii) inhibition or HMGB1 protein iii) inhibition of detoxifying enzyme glyoxalase 1 (GLO-1) Inhibition of HMGB1:				62,63
		PfHMGB1		ΔE = −96.57 kcal/mol	ΔG = −32.70 kcal/mol
		HsHMGB1		ΔE = −83.66 kcal/mol	ΔG = −21.65 kcal/mol
		An in vivo study on P. berghei-infected mice was conducted using root extract containing 11 as the major active ingredients. Parasite suppression: 86.37%
12	Glycosylated β-amino hydroxamates	Antiplasmodium Potent inhibition of Schizont maturation based on in vitro schizonticidal activity against P. falciparum at concentrations 2 and 50 µg/mL.				64
		Inhibition at 2 µg/mL: 12a = 100% 12b = 88.8% CQ = n/a		Inhibition at 50 µg/mL: 12a = 100% 12b = 100% CQ = 100%
13	Carbohydrate-fused thiochromans	Antiplasmodium Potent IC50 against P. falciparum CQ-sensitive 3D7 and CQ-resistant FCR3 strains depends on the tert-butyl substituent on the phenyl ring and the presence of hydrogen-bond acceptor from the endo face.				65–67
		13a		3D7 = 0.30 µM	FCR3 = 0.33 µM
		13b		3D7 = 1.33 µM	FCR3 = 0.33 µM
		13c		3D7 = 0.39 µM	FCR3 = 0.28 µM
		CQ		3D7 = 0.016 µM	FCR3 = 0.064 µM
		Percentage survival of parasite using plasmodial lactate dehydrogenase assay treated with 13a: Concentration 10 µM = −5.10% Concentration 1 µM = 25.26% ± 2.89%
14	Nucleoside analogs	Antiplasmodium Active inhibition of P. falciparum and human ADA, and P. falciparum and human purine nucleoside phosphorylase (PNP). ADA inhibition prevents the deamination of adenosine and deoxyadenosine into respective inosines, and PNP inhibition eliminates the activated human T-cells, leading to purine-less P. falciparum death.				68–70
		Dissociation constants (Kd):	14a 14b 14c	hADA = 0.11 nM hADA = 0.026 nM hPNP = 0.056 nM	pfADA = 0.08 nM pfADA = 0.038 nM pfPNP = 0.86 nM
			14d	hADA > 10,000 nM	pfADA = 0.43 nM
			14e	hADA > 10,000 nM	pfADA = 0.73 nM
15	5′-Carboxamidoadenosine derivatives	Antiplasmodium Potent IC50 against P. falciparum CQ-resistant K1 strain.				71
		15 = 1.8 µM		Artemisinin = 0.0051 µM
16	Nucleoside–thioglycoside hybrids	Antiplasmodium Potent IC50 against P. falciparum CQ-sensitive 3D7 and CQ-resistant RKL-9 strains with no significant hemolysis and cytotoxicity toward the human RAW cell line.				72
		16a		3D7 = 0.92 ± 1.8 µM	RKL-9 = 2.1 ± 1.3 µM
		16b		3D7 = 1.15 ± 1.5 µM	RKL-9 = 2.21 ± 1.3 µM
		CQ		3D7 = 0.025 µM	RKL-9 = 0.125 µM
		Cell survival:		16a = 55% at 500 µM concentration 16b = 60% at 500 µM concentration
17	N-Glycoside derivatives of piperazine-linked DHA	Antiplasmodium Potent IC50 against both P. falciparum CQ-sensitive D10 and CQ-resistant W-2 strains.				73
		17a		D10 = 0.87 ± 0.25 nM	W-2 = 0.71 ± 0.2 nM
		17b		D10 = 0.74 ± 0.34 nM	W-2 = 0.74 ± 0.3 nM
		17c		D10 = 0.66 ± 0.2 nM	W-2 = 0.58 ± 0.25 nM
		Artemisone		D10= 1.1 ± 0.4 nM	W-2 = 0.9 ± 0.4 nM
		DHA		D10 = 3.4 ± 1.6 nM	W-2 = 0.9 ± 0.4 nM

Mannose, tested on a rodent experimental cerebral malaria, was revealed to effectively inhibit the Plasmodium parasite by regulating multiple host immune responses. The mechanism of action employed the dependency of the blood-stage infection on glycolysis for energy and pathological immune responses.⁸⁰ Many previous studies support the effect of host metabolism on malarial infection, in which the parasite tolerance was influenced by several factors, including glucose consumption, caloric restriction, and a high-fat diet.^81–83

Biologically, glycosides could exploit the carbohydrate transport mechanisms within both the host and parasite during a malarial infection. One of the primary proposed mechanisms by which sugar moieties can enhance antimalarial activity is through interaction with the glucose transporter GLUT1, which is abundantly expressed in the erythrocyte membrane, and the parasite hexose transporter PfHT, which selectively transports glucose and fructose into the parasite. These transport proteins play a crucial role in the continuous glucose uptake into the infected erythrocytes and the parasite. Hence, compounds that can mimic glucose would be preferentially taken up into the parasite and eventually interrupt the parasite's metabolic pathways.^11,84–86 Some glycosylated compounds could also potentially inhibit the formation of hemozoin, a detoxification byproduct of hemoglobin digestion by the parasite. This involves direct interaction of the compound with the β-hematin that is formed during the heme detoxification process, thus preventing its crystallization into hemozoin.^{52,54,60,87,88}

One notable class of compounds that exemplifies potential antimalarial activity is C-glycosides 1a–d isolated from the marine Streptomyces sp. These compounds have shown potent antiplasmodial activity, likely due to the C-glycosyl and hydroxy groups of the benz[α]anthraquinone core skeleton. The structural configuration of sugar moiety facilitated the interaction of the compounds with target sites in the parasite, indicating their crucial role in enhancing efficacy. Nevertheless, the increased number of sugar moiety in 1b slightly reduced its potency.⁵¹ Compounds 2 and 3 extracted from the Solanaceae plant also exhibited significant antimalarial efficacy. The 6-OH of the sugar moiety in chaconine 2 was identified as essential for its antimalarial activity, leading to a more potent ED₅₀ and reduction in parasitemia, compared with 3. Notably, changing the 6-OH to 6-O-sulfate led to a loss of all activity against P. yoelii, highlighting the importance of specific sugar structures in the bioactivity of antimalarial compounds.⁵³

Additionally, the steroidal glucopyranoside 4 from Solanum nudum showed potential inhibition of β-hematin formation, demonstrating how sugar moieties can directly interfere with parasite metabolism.⁵⁴ Another steroidal glucoside 5 with per-O-acetylated β-D-arabinopyranoside demonstrated antiplasmodial activity against CQ-resistant strains better than the deacetylated derivative. However, further derivatization of 5 by changing the D-arabinose moiety into L-galactose led to its inactivity,⁵⁵ Nonetheless, the glycosylated steroidal compounds 4 and 5 demonstrated better antimalarial efficacy compared with the corresponding aglycones. The presence of the glycosyl group not only improved the solubility of the aglycones, but also facilitated entry into the parasite, thus enhancing the pharmacological effects. In the case of glycoside 6 isolated from Jacaranda glabra, the presence of glycosidic ester improved the antiplasmodial activity by 5-fold over the phenylacetic acid aglycone, accompanied by low toxicity on L-6 cells.^52,56 Moreover, studies on the hexadecyl ethers of disaccharides 7 against the CQ-resistant P. falciparum showed that the aglycone has no antiplasmodial potency, emphasizing the necessity of sugar moieties for exhibiting bioactivity.⁵⁷ These findings corroborate the significance of sugar substituents in antiplasmodial activity.

Further, the incorporation of sugar units into the organometallic ferrocenyl CQ-derived conjugate 8 resulted in enhanced activity against both CQ-sensitive and CQ-resistant strains of P. falciparum, with IC₅₀ values significantly lower than those of the reference CQ.^28,58 Likewise, a norbergenin derivative 9 from the Ebenaceae plant also exhibited better antiplasmodial activity with moderate cytotoxicity than CQ. The study emphasized the significance of the O-(3′-methylgalloyl) substituent on the sugar ring, which is crucial for its potency.⁵⁹ Another study based on C-glycosides 10a–c validated the higher potency of various glycosylated compounds over the sulfonamidyl and ureidyl aglycones. Altering the glucose moiety with mannose and xylose reduced the antiplasmodial activity, while compound 10b with an acetylated glucose moiety showed the highest potency and higher inhibition of heme polymerization than CQ, further highlighting the significance of the identity of the sugar component.^60,61 Furthermore, the bioactivity of glycyrrhizin 11 extracted from Glycyrrhiza glabra, which was attributed to its ability to disrupt membrane lipid rafts and inhibit detoxifying enzymes, demonstrates how sugar moieties can contribute to the overall mechanism of action.^62,63 The antiplasmodial activity of glycosylated β-amino hydroxamates 12, confirmed through in vitro studies, resulted in potent inhibition of schizont maturation. The study revealed that the glycosylated hydroxamates with a hexadecyl chain were more potent than the corresponding amino acids without the hexadecyl group. Interestingly, compound 12a with a glucofuranose exhibited higher schizonticidal activity than 12b, which possessed a galactopyranosyl moiety,⁶⁴ demonstrating the influence of the sugar composition on potency.

A study on carbohydrate-fused thiochromans 13a–c revealed that the survival rate of malaria parasites was dependent on the substituents of the thiochroman ring. The distinctive features attributed to the tert-butyl-substituted thiochroman ring and the benzyl-protected sugar contributes to the highly lipophilic and bulky character of these compounds. This likely affords greater stability to the compounds and resistance to enzymatic degradation, resulting in the most favorable activity and highest inhibition of parasite survival.^65,66,89 While having an alkyl substituent is essential for favorable bioactivity, lengthening the alkyl group beyond 4 carbons diminished the potency, suggesting that the longer alkyl chain and the increased hydrophobicity were less favorable for protein binding.^66,67 Further emphasizing the importance of the tert-butyl substituent, replacing it with a methyl or methoxy group markedly decreased the activity against both Plasmodium 3D7 and FCR3 strains.⁶⁷

The nucleoside analogs 14a–c have also shown the ability to inhibit both P. falciparum and human adenosine deaminase (pfADA and hADA), leading to the parasite death through purine depletion. The dissociation constants (K_d) for these interactions were remarkably low, indicating a strong affinity to their targets.^69,70 However, they are nonselective inhibitors, as they can also inhibit hADA and bovine enzymes. On the other hand, the alkylthio derivatives of 14a and 14b demonstrated highly selective inhibition of pfADA. The significance of sugar moieties has also been extended to artemisinin. Substituted 5′-carboxamidoadenosine 15 and thioglycoside-nucleoside conjugates 16 demonstrated higher IC₅₀ values compared with artemisinin,^71,72 while N-glycosides of piperazine-linked dihydroartemisinin (DHA) 17a–c showed improved pharmacokinetics over artemisinin. These modifications enhanced the solubility and cellular uptake of the drug, leading to improved efficacy against Plasmodium species. The incorporation of sugar units into the artemisinin structure not only aids in drug delivery but also facilitates interaction with target proteins within the parasite.⁷³

More recently, sevuparin (Fig. 2) is the only glyco-based compound that entered clinical trials for adjunct treatment of severe malaria in children.⁹⁰ Sevuparin inhibits merozoite invasion by binding to the parasite erythrocyte membrane protein, preventing parasite sequestration of the infected red blood cells (RBCs), particularly in vital organs.^91,92 It primarily interferes with the cytoadherence of infected erythrocytes, a critical factor in severe malaria pathogenesis, since the infected RBCs will preferably adhere to the endothelium of blood vessels, leading to microvascular obstruction and subsequent organ dysfunction.^93,94 Through the severe malaria in African children: A Research and Trials Consortium, phase I/II studies investigated the use of sevuparin alongside proguanil/atovaquone and provided insights into its safety profile.^7,95–98 However, its clinical application is curtailed due to serious side effects.⁹³ Nevertheless, information on its mechanisms and therapeutic effects continues to provide valuable insights that could enhance treatment protocols for malaria, particularly in resource-limited settings, where rapid intervention is critical.^7,91

Fig. 2.

Chemical structure of sevuparin.

The studies highlighted above represent novel carbohydrate-based adjunct treatments for malaria, offering a complementary strategy to existing antimalarials. The experimental results consistently support the notion that glycosylation can enhance the antimalarial efficacy of compounds through various mechanisms, including improved solubility, bioavailability, and interactions with parasite targets. These have been mainly attributed to the effect of the sugar moieties on the physiochemical properties of the parent compound. The presence of select sugar moieties has led to significant improvements in bioactivity, specifically in glycosides 1, 4–8, 10, 17. It is also essential to consider the structural characteristics of the sugar involved for enhanced bioactivity; the substituent of a sugar moiety might be significant (2, 3, 7, 9, 14–16), and the protected sugar could be more preferable over one that is deprotected (5, 10, 16). However, for some compounds, such as glycoside 12 and carbohydrate-derived thiochroman 13, the presence of alkyl or bulkier substituents could significantly affect hydrophobicity and membrane permeability. Overall, the application of glyco-based compounds improves the therapeutic efficacy of compounds, proposing those with the highest potential as lead compounds in treating malaria. However, further investigations, mainly through detailed molecular dynamics study and in vivo models, are needed to elucidate the detailed mechanisms of action and map the therapeutic framework of these compounds.

3. Synthesis of glycosides targeting malaria

The significant roles of glycosylated compounds in biological processes and potential therapeutic applications have led to the exploration of various glycosylation strategies. The approaches outlined below highlight notable advancements in the rational design of glycosylated derivatives, aiming to mimic biological substrates and selective drug delivery.

The thiochroman derivative 13c demonstrated high antimalarial activity, with IC₅₀ values of 0.46 μM. Madumo⁶⁶ successfully synthesized 13c with optimum hydrophilicity and lipophilicity as a potential antimalarial agent (Scheme 1). The glucose derivative 19, bearing an iodomethyl group at the 2-position, was treated with p-(tert-butyl)benzenethiol to yield sulfide 20. Subsequent Lewis acid-catalyzed intramolecular Friedel–Crafts alkylation produced thiochroman 21 with complete α-selectivity. Oxidation of 21 with OXONE then furnished the target sulfone 13c. This presents a method for constructing a thiochroman ring on the carbohydrate molecule, resulting in the formation of a thiochroman-based glycoside. The structural characteristics of the glycoside, which include a thiochroman ring, benzyl-protected sugar, and a lipophilic tert-butyl substituent, are identified as important factors for achieving lower IC₅₀ values.^65–67

scheme 1.

Synthesis of thiochroman derivative 13c: (i) NaH, Aryl thiol, DMF, rt, 10 min, (93%); (ii) BF₃·Et₂O, CH₂Cl₂, 0 °C, 15 min, (69%); (iii) OXONE®, Al₂O₃, CH₂Cl₂, rt, 12 h, (69%).^66,67

Another synthetic approach has led to the discovery of N-glycosylated DHA derivatives 17a–c involving the use of piperazine as a linker between the DHA and sugar moieties, which demonstrated the potential for improved therapeutic efficacy of artemisinin derivatives. These derivatives were synthesized through the Kotchetkov reaction, starting from the DHA-piperazine derivative (Scheme 2). Initially, α-trimethylsilyl acetal 22 was treated with trimethylsilyl bromide (TMSBr) in dichloromethane to form β-bromide 23, followed by an in situ reaction with anhydrous piperazine in the presence of triethylamine as a base to yield DHA-piperazine 26. However, this method proved unsatisfactory, leading to the adoption of an optimized process for preparing 17a. This improved approach uses an oxalyl chloride-catalytic dimethyl sulfoxide (DMSO) system to convert DHA 24 into β-chloride 25 in toluene, which is then treated with piperazine.⁷³ The application of a piperazine linker provided structural flexibility and enabled the precise coupling of aglycone and sugar moieties.

scheme 2.

Preparation of DHA-piperazine galactoside 17a. Route a: DHA TMS acetal 22, TMSBr, CH₂Cl₂, 0 °C, N₂, 30 min; Route b: DHA 24, (COCl)₂, cat. DMSO, toluene, N₂, rt, 30 min.⁷³

The synthesis of C-glycosides 10a–c with ureidyl and sulfonamidyl moieties which inherently exhibit antimalarial potency was established through the use of phenylbutenonyl linker to connect sugar moiety and the ureidyl/sulfonamidyl group. The per-O-acetylated β-C-glycosidic ketone 28 was synthesized through Knoevenagel condensation from unprotected sugar 27 under aqueous conditions, followed by acetylation, as shown in Scheme 3. The aminophenyl glycoside 30 was synthesized by first reacting 28 with 3-nitrobenzaldehyde to afford 3-nitrophenylbutenonyl glycopyranoside 29, followed by reduction of the nitro group with SnCl₂ under ultrasonic vibration to yield 3-aminophenylbutenonyl glycopyranoside 30. Further reaction with an appropriate nucleophile in the presence of Et₃N in CH₂Cl₂ led to the formation of 3 different C-glycoside derivatives containing sulfonamidyl 10a, thioureidyl 10b, and ureidyl 10c moieties.⁶⁰C-Glycosides offer structural features that are more resistant to degradation than O- and N-glycosides, thereby enhancing metabolic stability, while preserving bioavailability.⁹³ Potent activity against the CQ-resistant K1 strain of P. falciparum demonstrated by these derivatives, specifically 10b that is better than CQ, provides promising insights into C-glycosides as antimalarial candidates.

scheme 3.

Synthesis of C-glycosides 10a–c: (i) NaHCO_3, H₂O, 90 °C, 6 h, then Dowex resin (H⁺ form); (ii) DMAP, Ac₂O, pyridine, rt, 4 h; (iii) pyrrolidine (20 mol%), CH₂Cl₂, rt, 7 h; (iv) 3-nitrobenzaldehyde, SnCl₂·2H₂O, EtOH, 30 °C, 2 h; v) 10a: p-toluenesulfonyl chloride (p-TsCl), Et₃N, CH₂Cl₂, 0 to 30 °C; 10b: 2-methoxy-4-nitrophenyl isothiocyanate, Et₃N, CH₂Cl₂, rt; 10c: 4-methoxy-2-nitrophenyl isocyanate, Et₃N, CH₂Cl₂, rt, then NaOMe, MeOH, rt, 10 to 20 min^60,99

The chemical synthesis of antimalarial glycosides is continuously progressing, as exemplified by these 3 different synthetic approaches. These strategies provide a glimpse into the broader advancements in antimalarial research incorporating glycosides. Integrating these strategies with ongoing advancements in drug development and biological evaluation will propel the discovery of new antimalarial treatments, reinforcing the global fight against malaria.

4. Conclusion

This review presented an overview of the significance of glycosides as promising therapeutic candidates in antimalarial research. Research into adjunct therapies for malaria through glycosides and organic synthesis is gaining attention based on the proven potency of glycosylated compounds, making antimalarial drug discovery advancements more apparent. Nevertheless, further research is essential to elucidate and precisely determine the mechanism of action by which these compounds exert their biological effects. Advancements in high-throughput computing and high-resolution biological techniques should be exploited to characterize precise interactions with biological targets and improve formulation strategies, paving the way to develop more effective antimalarial therapies.

Funding

This work was supported by the South Asia Research Hub of the Foreign, Commonwealth and Development Office (FCDO), Government of the United Kingdom [ST-2024-001]. The views expressed in this report, however, do not necessarily reflect the official policies of the Government of the United Kingdom.

Siti Nur Hidayah Jamil

Completed her Bachelor's degree in Chemistry at The University of Manchester, United Kingdom and currently pursuing her PhD in Material Science and Engineering through a Joint-Degree program between Universiti Kebangsaan Malaysia and Gifu University, Japan. Her present work specializes in computational chemistry, organic synthesis, and antimalarial studies, specifically based on curcumin derivative compounds. She is also a graduate member of the Royal Society of Chemistry and the American Chemical Society.

Emil Salim

Currently a PhD student at Gifu University, Japan, with previous experience as an organic chemistry assistant professor and a lecturer at Universitas Andalas, Indonesia. He received a BSc in Chemistry from the Universitas Andalas in 2010 and an MSc in Synthesis, Catalysis, and Sustainable Chemistry from a double-degree program between Université Claude-Bernard Lyon 1, France, and Institut Teknologi Bandung, Indonesia in 2014. His current research interest is the design of novel derivatives from chloroquine and artemisinin as potential antimalarial agents.

Natsuhisa Oka

Received his PhD from the University of Tokyo in 2003, he subsequently worked as a postdoctoral fellow at the University of California, San Diego, and at Johns Hopkins University from 2003 to 2004. In 2005, he returned to the University of Tokyo, where he worked as an assistant professor. In 2009, he joined the Faculty of Engineering at Gifu University, where he served as an associate professor before being promoted to full professor in 2023. His research interests are centered on the chemistry of biomolecules, with particular emphasis on nucleic acids and carbohydrates.

Su Datt Lam

Earned his Ph.D. in Structural and Molecular Biology from University College London and currently leads a research group at Universiti Kebangsaan Malaysia, specializing in structural bioinformatics. His research focuses on understanding the impact of mutations on protein structures, particularly in the areas of host-viral interactions, antimicrobial resistance, and crop breeding. He has coauthored over 30 articles in high-impact journals, including Nature Communications and Nucleic Acids Research. Su Datt is also an executive committee member of the Malaysian Society of Bioinformatics and Computational Biology and serves as an editor for the Malaysian Journal of Biochemistry and Molecular Biology.

Shevin Rizal Feroz

Graduated with PhD in Biochemistry from Universiti Malaya, Malaysia in 2015, he is specialized in biochemistry and biophysics. His research focuses on biomolecular interactions, particularly the binding characteristics of various compounds though biophysical experiments. He has published numerous articles in high-impact journals and is known for his work on the biochemical and structural characterization of ligand-protein interactions.

Amatul Hamizah Ali

Currently a postdoctoral researcher specializing in biochemistry and malaria drug discovery. She completed her PhD in Biochemistry from Universiti Kebangsaan Malaysia in 2018. Her work focuses on discovering new antimalarial drugs and understanding the bioactivity of natural compounds, including her publications on the exploration of protein kinases in drug discovery.

Jalifah Latip Currently an Associate Professor specializing in organic chemistry and natural products. She graduated from the University of Strathclyde, United Kingdom with an MSc in Pharmacology and a PhD in Pharmaceutical Sciences, and currently a registered chemist under the Malaysian Institute of Chemistry and a member of Malaysian Natural Products Society. Her research focuses on molecular structure determination, and exploring bioactive natural and synthetic compounds.

Author notes

Conflict of interest statement. None declared.