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Drug Design, Development and Therapy 2023Malaria remains to be a national and global challenge and priority, as stated in the strategic plan of the Indonesian Ministry of Health and Sustainable Development... (Review)
Review
Malaria remains to be a national and global challenge and priority, as stated in the strategic plan of the Indonesian Ministry of Health and Sustainable Development Goals. In Indonesia, it is targeted that malaria elimination can be achieved by 2030. Unfortunately, the development and spread of antimalarial resistance inflicts a significant risk to the national malaria control programs which can lead to increased malaria morbidity and mortality. In Indonesia, resistance to widely used antimalarial drugs has been reported in two human species, and . With the exception of artemisinin, resistance has surfaced towards all classes of antimalarial drugs. Initially, chloroquine, sulfadoxine-pyrimethamine, and primaquine were the most widely used antimalarial drugs. Regrettably, improper use has supported the robust spread of their resistance. Chloroquine resistance was first reported in 1974, while sulfadoxine-pyrimethamine emerged in 1979. Twenty years later, most provinces had declared treatment failures of both drugs. Molecular epidemiology suggested that variations in and genes were associated with chloroquine resistance, while and genes were correlated with sulfadoxine-pyrimethamine resistance. Additionally, and of genes appeared to be early warning sign to artemisinin resistance. Here, we reported mechanisms of antimalarial drugs and their development of resistance. This insight could provide awareness toward designing future treatment guidelines and control programs in Indonesia.
Topics: Humans; Antimalarials; Indonesia; Chloroquine; Artemisinins
PubMed: 37431492
DOI: 10.2147/DDDT.S403672 -
Nature Communications Oct 2023Long-acting injectable medications, such as atovaquone, offer the prospect of a "chemical vaccine" for malaria, combining drug efficacy with vaccine durability. However,...
Long-acting injectable medications, such as atovaquone, offer the prospect of a "chemical vaccine" for malaria, combining drug efficacy with vaccine durability. However, selection and transmission of drug-resistant parasites is of concern. Laboratory studies have indicated that atovaquone resistance disadvantages parasites in mosquitoes, but lack of data on clinically relevant Plasmodium falciparum has hampered integration of these variable findings into drug development decisions. Here we generate atovaquone-resistant parasites that differ from wild type parent by only a Y268S mutation in cytochrome b, a modification associated with atovaquone treatment failure in humans. Relative to wild type, Y268S parasites evidence multiple defects, most marked in their development in mosquitoes, whether from Southeast Asia (Anopheles stephensi) or Africa (An. gambiae). Growth of asexual Y268S P. falciparum in human red cells is impaired, but parasite loss in the mosquito is progressive, from reduced gametocyte exflagellation, to smaller number and size of oocysts, and finally to absence of sporozoites. The Y268S mutant fails to transmit from mosquitoes to mice engrafted with human liver cells and erythrocytes. The severe-to-lethal fitness cost of clinically relevant atovaquone resistance to P. falciparum in the mosquito substantially lessens the likelihood of its transmission in the field.
Topics: Humans; Animals; Mice; Atovaquone; Parasites; Antimalarials; Malaria; Malaria, Falciparum; Plasmodium falciparum; Anopheles; Antiparasitic Agents; Vaccines
PubMed: 37828012
DOI: 10.1038/s41467-023-42030-x -
Parasitology Oct 2023Helminth infections are ubiquitous in grazing ruminants and cause significant costs due to production losses. Moreover, anthelmintic resistance (AR) in parasites is now... (Review)
Review
Helminth infections are ubiquitous in grazing ruminants and cause significant costs due to production losses. Moreover, anthelmintic resistance (AR) in parasites is now widespread throughout Europe and poses a major threat to the sustainability of modern ruminant livestock farming. Epidemiological data on the prevalence and distribution of gastrointestinal nematodes, cestodes and liver- and rumen-flukes in Italian small ruminants are outdated and fragmentary. However, anthelmintics are commonly used to control these infections and often without prior diagnosis. Compared to other European countries, few reports of AR in small ruminants against levamisole, ivermectin and benzimidazoles have been published in Italy, but recent studies suggest that this phenomenon is spreading. Increased and integrated research efforts in developing innovative approaches to control helminth infections and AR are needed and must be tailored to the peculiarities of each context in order to be effectively implemented. This manuscript provides an overview on helminth prevalence and distribution, sustainable treatment strategies and integrated control approaches in small ruminants in Italy. The implementation of targeted treatments and targeted selective treatments is discussed based on different parameters, such as fecal egg count, degree of anaemia (FAMACHA method), milk production and body condition score. In addition, several Italian studies have also investigated the implementation of alternative strategies such as the use of different natural bioactive compounds or genetic selection for resistance and resilience to helminth infections. These concrete solutions for helminth management in small ruminant farms in the country are reported and discussed, representing a valid example for other Mediterranean countries.
Topics: Animals; Drug Resistance; Anthelmintics; Ruminants; Helminths; Nematoda; Nematode Infections
PubMed: 37039466
DOI: 10.1017/S0031182023000343 -
Frontiers in Cellular and Infection... 2023Leishmaniasis is a neglected tropical disease with a wide spectrum of clinical manifestations, ranging from visceral to cutaneous, with millions of new cases and... (Review)
Review
Leishmaniasis is a neglected tropical disease with a wide spectrum of clinical manifestations, ranging from visceral to cutaneous, with millions of new cases and thousands of deaths reported each year. The species of and the immune response of the host determine the severity of the disease. Leishmaniasis remains challenging to diagnose and treat, and there is no vaccine available. Several studies have been conducted on the use of herbal medicines for the treatment of leishmaniasis. Natural products can provide an inexhaustible source of chemical diversity with therapeutic potential. Terpenes are a class of natural products derived from a single isoprene unit, a five-carbon compound that forms the basic structure of isoprenoids. This review focuses on the most important and recent advances in the treatment of parasites of the genus with different subclasses of terpenes. Several mechanisms have been proposed in the literature, including increased oxidative stress, immunomodulatory role, and induction of different types of parasite cell death. However, this information needs to be brought together to provide an overview of how these compounds can be used as therapeutic tools for drug development and as a successful adjuvant strategy against sp.
Topics: Humans; Terpenes; Antiprotozoal Agents; Leishmania; Leishmaniasis; Cell Death; Biological Products
PubMed: 37799331
DOI: 10.3389/fcimb.2023.1260448 -
Scientific Reports Dec 2023Parasitic roundworms cause significant sickness and mortality in animals and humans. In livestock, these nematodes have severe economic impact and result in losses in...
Parasitic roundworms cause significant sickness and mortality in animals and humans. In livestock, these nematodes have severe economic impact and result in losses in food production on a global scale. None of the currently available drugs ideally suit all treatment circumstances, and the development of drug-resistant nematode strains has become a challenge to control the infection. There is an urgent need to develop novel anthelmintic compounds. According to our previous report, N-methylbenzo[d]oxazol-2-amine (1) showed anthelmintic activity and lowest cytotoxicity. In this study, in vivo anthelmintic properties were evaluated using Trichinella spiralis infected mice. Toxicity was evaluated using the rats and mode of action using molecular docking and metabolomics approaches. The in vivo results demonstrate that a dose of 250 mg/kg reduced the T. spiralis abundance in the digestive tract by 49%. The 250 mg/kg Albendazole was served as control. The relatively low acute toxicity was categorized into chemical category 5, with an LD greater than 2000 mg/kg body. Molecular docking analysis showed the T. spiralis tubulin beta chain and glutamate-gated channels might not be the main targets of compound 1. Metabolomics analysis was used to explain the effects of compound 1 on the T. spiralis adult worm. The results demonstrated that compound 1 significantly up-regulated the metabolism of purine, pyrimidine and down-regulated sphingolipid metabolism. In conclusion, compound 1 could be a potential molecule for anthelmintic development. The bioavailability, pharmacokinetics, and absorption of this compound should be studied further to provide information for its future efficacy improvement.
Topics: Humans; Mice; Rats; Animals; Molecular Docking Simulation; Anthelmintics; Albendazole; Nematoda; Trichinella spiralis
PubMed: 38129499
DOI: 10.1038/s41598-023-50305-y -
International Journal of Pharmaceutics Sep 2023In this paper we report a successful example of combining drugs through cocrystallization. Specifically, the novel solid is formed by two anthelminthic drugs, namely...
In this paper we report a successful example of combining drugs through cocrystallization. Specifically, the novel solid is formed by two anthelminthic drugs, namely praziquantel (PZQ) and niclosamide (NCM) in a 1:3 molar ratio, and it can be obtained through a sustainable one-step mechanochemical process in the presence of micromolar amounts of methanol. The novel solid phase crystallizes in the monoclinic space group of P2/c, showing one PZQ and three NCM molecules linked through homo- and heteromolecular hydrogen bonds in the asymmetric unit, as also attested by SSNMR and FT-IR results. A plate-like habitus is evident from scanning electron microscopy analysis with a melting point of 202.89 °C, which is intermediate to those of the parent compounds. The supramolecular interactions confer favorable properties to the cocrystal, preventing NCM transformation into the insoluble monohydrate both in the solid state and in aqueous solution. Remarkably, the PZQ - NCM cocrystal exhibits higher anthelmintic activity against in vitro S. mansoni models than corresponding physical mixture of the APIs. Finally, due to in vitro promising results, in vivo preliminary tests on mice were also performed through the administration of minicapsules size M.
Topics: Animals; Mice; Praziquantel; Niclosamide; Antiparasitic Agents; Pharmaceutical Preparations; Spectroscopy, Fourier Transform Infrared; Anthelmintics; Schistosoma mansoni
PubMed: 37579827
DOI: 10.1016/j.ijpharm.2023.123315 -
Molecules (Basel, Switzerland) Nov 2023Peptide compounds play a significant role in medicinal chemistry as they can inhibit the activity of species that cause malaria. This literature review summarizes the... (Review)
Review
Peptide compounds play a significant role in medicinal chemistry as they can inhibit the activity of species that cause malaria. This literature review summarizes the isolation of antimalarial peptides, the synthesis method with the detailed structure and sequences of each peptide, and discusses the biological activity of the isolated and synthesized compounds. The synthetic routes and reactions for cyclic and linear antimalarial peptides are systematically highlighted in this review including preparing building blocks, protection and deprotection, coupling and cyclization reactions until the target compound is obtained. Based on the literature data and the results, this review's aim is to provide information to discover and synthesize more antimalarial peptide for future research.
Topics: Humans; Antimalarials; Peptides; Malaria; Cyclization; Chemistry, Pharmaceutical; Peptides, Cyclic
PubMed: 38067508
DOI: 10.3390/molecules28237778 -
European Journal of Medicinal Chemistry Oct 2023A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines...
A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines obtained exhibited in vitro activity in the low- or sub-micromolar range against (i) hepatic stages of Plasmodium berghei, (ii) erythrocytic forms of Plasmodium falciparum, and (iii) early and mature gametocytes of Plasmodium falciparum. The most active compound, having a meta-fluorocinnamoyl group linked to the acridine core, was 20- and 120-fold more potent, respectively, against the hepatic and gametocyte stages of Plasmodium infection than the reference drug, primaquine. Moreover, no cytotoxicity towards mammalian and red blood cells at the concentrations tested was observed for any of the compounds under investigation. These novel conjugates represent promising leads for the development of new multi-target antiplasmodials.
Topics: Animals; Aminacrine; Aminoacridines; Antimalarials; Mammals; Plasmodium berghei; Plasmodium falciparum; Primaquine
PubMed: 37390511
DOI: 10.1016/j.ejmech.2023.115575 -
Microbiology Spectrum Aug 2023Schistosomiasis is a parasitic disease that afflicts approximately 250 million people worldwide. There is an urgent demand for new antiparasitic agents because...
Schistosomiasis is a parasitic disease that afflicts approximately 250 million people worldwide. There is an urgent demand for new antiparasitic agents because praziquantel, the only drug available for the treatment of schistosomiasis, is not universally effective and may derail current progress toward the WHO goal of eliminating this disease as a public health problem by 2030. Nifuroxazide (NFZ), an oral nitrofuran antibiotic, has recently been explored to be repurposed for parasitic diseases. Here, , , and studies were conducted to evaluate the activity of NFZ on Schistosoma mansoni. The study showed significant antiparasitic activity, with 50% effective concentration (EC) and 90% effective concentration (EC) values of 8.2 to 10.8 and 13.7 to 19.3 μM, respectively. NFZ also affected worm pairing and egg production and induced severe damage to the tegument of schistosomes. , a single oral dose of NFZ (400 mg/kg of body weight) to mice harboring either prepatent or patent S. mansoni infection significantly reduced the total worm burden (~40%). In patent infection, NFZ achieved a high reduction in the number of eggs (~80%), but the drug caused a low reduction in the egg burden of animals with prepatent infection. Finally, results from target fishing methods predicted that serine/threonine kinases could be one of the potential targets for NFZ in S. mansoni. Overall, the present study revealed that NFZ possesses antischistosomal properties, mainly in terms of egg burden reduction in animals with patent S. mansoni infection. The increasing recognition of the burden imposed by helminthiasis, associated with the limited therapeutic arsenal, has led to initiatives and strategies to research and develop new drugs for the treatment of schistosomiasis. One of these strategies is drug repurposing, which considers low-risk compounds with potentially reduced costs and shorter time for development. In this study, nifuroxazide (NFZ) was evaluated for its anti-Schistosoma mansoni potential through , , and studies. , NFZ affected worm pairing and egg production and induced severe damage to the tegument of schistosomes. , a single oral dose of NFZ (400 mg/kg) to mice harboring either prepatent or patent S. mansoni infection significantly reduced the total worm burden and egg production. investigations have identified serine/threonine kinases as a molecular target for NFZ. Collectively, these results implied that NFZ might be a potential therapeutic candidate for the treatment of schistosomiasis.
Topics: Animals; Mice; Schistosomicides; Schistosomiasis mansoni; Schistosoma mansoni; Schistosomiasis; Nitrofurans; Threonine; Serine
PubMed: 37409934
DOI: 10.1128/spectrum.01393-23 -
Dalton Transactions (Cambridge, England... Nov 2023Artesunate (Ars) is a semisynthetic antimalarial drug and is a part of the artemisinin-based combination therapy arsenal employed for malaria treatment. The drug...
Artesunate (Ars) is a semisynthetic antimalarial drug and is a part of the artemisinin-based combination therapy arsenal employed for malaria treatment. The drug functions mainly by activation of its endoperoxide bridge leading to increased oxidative stress in malaria parasites. The purpose of this study was to ascertain the antiparasitic effects of combining ferrocene and Ars short or long chain ester or amide linkages (C1-C4). The compounds were evaluated for growth inhibition activity on the apicomplexan parasites, () and (). All the complexes demonstrated good activity against with IC values in the low micromolar range (0.28-1.2 μM) and good to excellent antimalarial activity against a chloroquine sensitive strain of (NF54). Further investigations on revealed that the likely mode of action (MoA) is through the generation of reactive oxygen species. Additionally, immunofluorescence microscopy suggested a novel change in the morphology of the parasite by complex C3, an artesunate-ferrocenyl ethyl amide complex. The complexes were not cytotoxic or showed low cytotoxicity to two normal cell lines tested.
Topics: Humans; Artesunate; Antiparasitic Agents; Antimalarials; Malaria, Falciparum; Malaria; Plasmodium falciparum; Amides
PubMed: 37681434
DOI: 10.1039/d3dt02254d