Preliminary insight on diarylpentanoids as potential antimalarials: In silico, in vitro pLDH and in vivo zebrafish toxicity assessment.

Malaria remains a major public health problem worldwide, including in Southeast Asia. Chemotherapeutic agents such as chloroquine (CQ) are effective, but problems with drug resistance and toxicity have necessitated a continuous search for new effective antimalarial agents. Here we report on a virtual screening of ∼300 diarylpentanoids and derivatives, in search of potential Plasmodium falciparum lactate dehydrogenase (PfLDH) inhibitors with acceptable drug-like properties. Several molecules with binding affinities comparable to CQ were chosen for in vitro validation of antimalarial efficacy. Among them, MS33A, MS33C and MS34C are the most promising against CQ-sensitive (3D7) with EC50 values of 1.6, 2.5 and 3.1 µM, respectively. Meanwhile, MS87 (EC50 of 1.85 µM) shown the most active against the CQ-resistant Gombak A strain, and MS33A and MS33C the most effective P. knowlesi inhibitors (EC50 of 3.6 and 5.1 µM, respectively). The in vitro cytotoxicity of selected diarylpentanoids (MS33A, MS33C, MS34C and MS87) was tested on Vero mammalian cells to evaluate parasite selectivity (SI), showing moderate to low cytotoxicity (CC50 > 82 µM). In addition, MS87 exhibited a high SI and the lowest resistance index (RI), suggesting that MS87 may exert effective parasite inhibition with low resistance potential in the CQ-resistant P. falciparum strain. Furthermore, the in vivo toxicity of the molecules on early embryonic development, the cardiovascular system, heart rate, motor activity and apoptosis were assessed in a zebrafish animal model. The overall results indicate the preliminary potential of diarylpentanoids, which need further investigation for their development as new antimalarial agents.

Exploring diverse frontiers: Advancements of bioactive 4-aminoquinoline-based molecular hybrids in targeted therapeutics and beyond.

Amongst heterocyclic compounds, quinoline and its derivatives are advantaged scaffolds that appear as a significant assembly motif for developing new drug entities. Aminoquinoline moiety has gained significant attention among researchers in the 21stcentury. Considering the biological and pharmaceutical importance of aminoquinoline derivatives, herein, we review the recent developments (since 2019) in various biological activities of the 4-aminoquinoline scaffold hybridized with diverse heterocyclic moieties such as quinoline, pyridine, pyrimidine, triazine, dioxine, piperazine, pyrazoline, piperidine, imidazole, indole, oxadiazole, carbazole, dioxole, thiazole, benzothiazole, pyrazole, phthalimide, adamantane, benzochromene, and pyridinone. Moreover, by gaining knowledge about SARs, structural insights, and molecular targets, this review may help medicinal chemists design cost-effective, selective, safe, and more potent 4-aminoquinoline hybrids for diverse biological activities.

Chalcone Mannich base derivatives: synthesis, antimalarial activities against Plasmodium knowlesi, and molecular docking analysis.

Development and discovery of new antimalarial drugs are needed to overcome the multi-resistance of Plasmodium parasites to commercially available drugs. Modifying the substitutions on the amine groups has been shown to increase antimalarial activities and decrease cross-resistance with chloroquine. In this study, we have synthesized several chalcone derivatives via the substitution of aminoalkyl groups into the aromatic chalcone ring using the Mannich-type reaction. The chalcone derivatives were evaluated for their antimalarial properties against Plasmodium knowlesi A1H1 and P. falciparum 3D7, as well as their molecular docking on Plasmodium falciparum dihydrofolate reductases-thymidylate synthase (PfDHFR-TS). Data from in vitro evaluation showed that chalcone Mannich-type base derivatives 2a, 2e, and 2h displayed potential antimalarial activities against P. knowlesi with EC50 of 2.64, 2.98, and 0.10 µM, respectively, and P. falciparum 3D7 with EC50 of 0.08, 2.69, and 0.15 µM, respectively. The synthesized compounds 2a, 2e, and 2h exerted high selectivity index (SI > 10) values on the A1H1 and 3D7 strains. The molecular docking analysis on PfDHFR-TS supported the in vitro assay of 2a, 2e, and 2h by displaying CDOCKER energy of -48.224, -43.292, and -45.851 kcal mol-1. Therefore, the evidence obtained here supports that PfDHFR-TS is a putative molecular target for the synthesized compound.

Curcumin and Its Derivatives as Potential Antimalarial and Anti-Inflammatory Agents: A Review on Structure-Activity Relationship and Mechanism of Action.

Curcumin, one of the major ingredients of turmeric (Curcuma longa), has been widely reported for its diverse bioactivities, including against malaria and inflammatory-related diseases. However, curcumin's low bioavailability limits its potential as an antimalarial and anti-inflammatory agent. Therefore, research on the design and synthesis of novel curcumin derivatives is being actively pursued to improve the pharmacokinetic profile and efficacy of curcumin. This review discusses the antimalarial and anti-inflammatory activities and the structure-activity relationship (SAR), as well as the mechanisms of action of curcumin and its derivatives in malarial treatment. This review provides information on the identification of the methoxy phenyl group responsible for the antimalarial activity and the potential sites and functional groups of curcumin for structural modification to improve its antimalarial and anti-inflammatory actions, as well as potential molecular targets of curcumin derivatives in the context of malaria and inflammation.

Seroprevalence of Zika Virus among Forest Fringe Communities in Peninsular Malaysia and Sabah: General Population-Based Study.

Zika virus (ZIKV) has had a history in Malaysia since its first isolation in 1966. However, it is believed that the immunity status among forest fringe communities has been underreported. We conducted cross-sectional surveillance of forest fringe communities from 10 Orang Asli villages and their peripheral communities in Perak, Pahang, and Sabah in Malaysia. A total of 706 samples were collected from 2019 to 2020 and screened for ZIKV exposure using an anti-ZIKV IgG ELISA kit. A neutralization assay against ZIKV was used to confirm the reactive samples. The seroprevalence results reported from the study of this population in Malaysia were 21.0% (n = 148, 95% CI, 0.183-0.273) after confirmation with a foci reduction neutralization test. The presence of neutralizing antibodies provides evidence that the studied forest fringe communities in Malaysia have been exposed to ZIKV. Multivariate analysis showed that those older than 44 years and those with an education below the university level had been exposed significantly to ZIKV. In addition, higher seropositivity rates to ZIKV were also reported among secondary school students from Bentong (Pahang) and residents from Segaliud (Sabah). No associations were identified between Zika seropositivity and gender, household size, house radius to the jungle, and income level. The presence of neutralizing antibodies against ZIKV among the study population might indicate that the causative pathogen had already circulated widely in forest fringe regions. Intervention for vector control, protection from mosquito bites, and awareness improvement should be encouraged in this population.

Prevalence of simian malaria among macaques in Malaysia (2000-2021): A systematic review.

BACKGROUND: The aim of Malaysia to eliminate malaria nationwide by 2020 seems need to be prolonged. Whilst Malaysia has successfully eliminated human malaria transmission, simian malaria parasites such as Plasmodium knowlesi, P. cynomolgi, P. inui and P. cynomolgi are the emerging cause of malaria in humans. The epidemiological study of simian malaria in primates provides useful information in identifying the risk of human-macaques Plasmodium infection. METHODOLOGY/PRINCIPAL FINDINGS: This study was performed to gather all available data in terms of simian malaria epidemiology study among macaques in Malaysia over the last two decades. This systematic review was conducted according to the PRISMA guidelines to select appropriate articles as references. Data searches were performed through international databases such as Google Scholar, PubMed, CrossRef, Scopus, Web of Science and Science Direct for original articles published from 2000 until 2021. The review identified seven simian malaria epidemiology studies in Malaysia over the 20-year study period. Most studies were conducted in Peninsular Malaysia (5/7; 71%) followed by East Malaysia (2/7; 29%). All studies showed positive detection of Plasmodium parasites in macaques. The most prevalent Plasmodium species in macaques was P. inui (49.27%) and the least prevalent was P. fieldi (4.76%). The prevalence of simian malaria was higher in East Malaysia compared to Peninsular Malaysia. The mono, dual and triple infection types were the most common among macaques. CONCLUSION/SIGNIFICANCE: The non-human primates like macaques are the reservoir of simian plasmodium in Malaysia. Hence, the study of host epidemiology is an important insight to public health management as there is a high occurrence of simian malaria in Malaysia. The right measurement can be taken as well to prevent the transmission of simian malaria from macaques to humans.

Data of knowledge towards Zika Virus infection in Sabah, Malaysia.

This dataset presents a cross-sectional survey and was conducted to assess the knowledge on Zika Virus infection among adults in Sabah. The data were collected from December 2019 to February 2021, 274 adults living in forest fringe communities were interviewed by trained personnel and have completed the distributed questionnaires. SPSS version 27.0 was used to analyzed the data. These data could serve as auxiliary information and/or research data for other researchers in Sabah. It could also serve as guide or reference data to other researchers outside Sabah who may be interested in carrying out similar research in other state.

Synthesis, Molecular Docking, and Antimalarial Activity of Hybrid 4-Aminoquinoline-pyrano[2,3-c]pyrazole Derivatives.

Widespread resistance of Plasmodium falciparum to current artemisinin-based combination therapies necessitate the discovery of new medicines. Pharmacophoric hybridization has become an alternative for drug resistance that lowers the risk of drug-drug adverse interactions. In this study, we synthesized a new series of hybrids by covalently linking the scaffolds of pyrano[2,3-c]pyrazole with 4-aminoquinoline via an ethyl linker. All synthesized hybrid molecules were evaluated through in vitro screenings against chloroquine-resistant (K1) and -sensitive (3D7) P. falciparum strains, respectively. Data from in vitro assessments showed that hybrid 4b displayed significant antiplasmodial activities against the 3D7 strain (EC50 = 0.0130 ± 0.0002 µM) and the K1 strain (EC50 = 0.02 ± 0.01 µM), with low cytotoxic effect against Vero mammalian cells. The high selectivity index value on the 3D7 strain (SI > 1000) and the K1 strain (SI > 800) and the low resistance index value from compound 4b suggested that the pharmacological effects of this compound were due to selective inhibition on the 3D7 and K1 strains. Molecular docking analysis also showed that 4b recorded the highest binding energy on P. falciparum lactate dehydrogenase. Thus, P. falciparum lactate dehydrogenase is considered a potential molecular target for the synthesized compound.

Influence of physico-chemical characteristics of rembau river, peninsular Malaysia, on congregating Pteroptyx fireflies.

We studied the water quality of the riparian firefly sanctuary of Sungai Rembau, or Rembau River, in Negeri Sembilan, Malaysia, from January 2018 to November 2018 to determine the possible influence of the physico-chemical characteristics of the water on the firefly populations living within the sanctuary. We set up a total of five water quality sampling stations and 10 firefly sampling stations along the river. Dissolved oxygen (DO), temperature, pH and electrical conductivity (EC) were measured in situ, while chemical oxygen demand (COD), total suspended solids (TSS), biochemical oxygen demand (BOD) and ammonia-nitrogen (NH3-N) were analysed in the laboratory. Firefly samples were collected using a sweep net at both day and night for 1 min. Sungai Rembau was categorized as Class II on the Malaysian water quality index (WQI), which indicates slight pollution. Except for EC and DO, the water quality parameter values were not significantly different (p > 0.05) between the sampling stations. A total of 529 firefly individuals consisting of Pteroptyx tener (n = 525, 99.24%), P. malaccae (n = 3, 0.57%) and P. asymmetria (n = 1, 0.19%) were collected. There was significant correlation between firefly abundance and BOD (r = - 0.198, p < 0.05), NH3-N (r = - 0.150, p < 0.05) and pH (r = 0.408, p < 0.05). The results show that the firefly populations in Sungai Rembau are sensitive to organic compounds, which may be present in the form of pollutants from anthropogenic activities near their natural habitat.

Draft Genome Sequence of Leptospira yasudae Strain BJ3, Isolated from the Soil of an Ex Situ Wild Animal Conservation Area.

Previously, a novel Leptospira strain (BJ3) was isolated from the soil of an ex situ wild animal conservation area in Perak, Malaysia. Molecular identification via whole-genome sequencing confirmed that the strain was Leptospira yasudae. Here, we report the draft genome sequence of L. yasudae strain BJ3.

Dual Anti-Malarial and GSK3ß-Mediated Cytokine-Modulating Activities of Quercetin Are Requisite of Its Potential as a Plant-Derived Therapeutic in Malaria.

Although death in malaria is attributed to cerebrovascular blockage and anaemia, overwhelming cytokine production can contribute to the severity of the disease. Therefore, mitigation of dysregulated inflammatory signalling may provide further benefit for malaria treatment. Quercetin (3,3',4',5,7-pentahydroxyflavone) is known to inhibit glycogen synthase kinase-3ß (GSK3ß), a potent regulator of both pro- and anti-inflammatory effects. Quercetin is therefore a potential therapeutic to modulate the imbalanced cytokine production during malarial infection. Anti-malarial effects of quercetin were evaluated in murine models of severe and cerebral malaria using Plasmodium berghei NK65 and ANKA strains, respectively. Western blotting and analysis of cytokines were carried out to determine the GSK3ß-mediated cytokine-modulating effects of quercetin in infected animals. Quercetin (25 mg/kg BW) treatment in P. berghei NK65-infected animals resulted in 60.7 ± 2.4% suppression of parasitaemia and significantly decreased serum levels of TNF-α and IFN-γ, whilst levels of IL-10 and IL-4 were elevated significantly. Western analysis revealed that pGSK3ß (Ser9) increased 2.7-fold in the liver of quercetin-treated NK65-infected animals. Treatment of P. berghei ANKA-infected mice with quercetin (15 mg/kg BW) increased (2.3-fold) pGSK3ß (Ser9) in the brains of infected animals. Quercetin is a potential plant-derived therapeutic for malaria on the basis that it can elicit anti-malarial and GSK3ß-mediated cytokine-modulating effects.

Data on antiplasmodial and stage-specific inhibitory effects of Aromatic (Ar)-Turmerone against Plasmodium falciparum 3D7.

Aromatic (ar)-turmerone is one of the aromatic constituents abundant in turmeric essential oil from Curcuma longa. Ar-turmerone exhibited anti-inflammatory properties. So far, antiplasmodial data for ar-turmerone is still not reported. The data showed the in vitro antiplasmodial effect of ar-turmerone against Plasmodium falciparum 3D7 (chloroquine-sensitive) via Plasmodium lactate dehydrogenase assay (pLDH) and cytotoxic effect against Vero mammalian kidney cells using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) colourimetric assay. Selectivity indexes of ar-turmerone were calculated based on inhibition concentration at 50% of parasite growth (IC50) from MTT and pLDH assays and the effects of ar-turmerone were compared to the antimalarial reference drug chloroquine diphosphate. The inhibitory effect of ar-turmerone at the intraerythrocytic stages of plasmodial lifecycles was evaluated via a stage-dependant susceptibility test. The antiplasmodial and cytotoxic activities of ar-turmerone revealed IC50 values of 46.8 ± 2.4 µM and 820.4 ± 1.5 µM respectively. The selectivity index of ar-turmerone was 17.5. Ar-turmerone suppressed the ring-trophozoite transition stage of the intraerythrocytic life cycle of P. falciparum 3D7.

Detection of Leptospira kmetyi at recreational areas in Peninsular Malaysia.

Humans can be infected by pathogenic Leptospira through contact with infected animals or contaminated environments. Recreational exposure has been associated with human leptospirosis; however, there is a lack of information on the distribution of Leptospira spp. in recreational areas. Thus, we conducted this study to detect and describe the distributions of Leptospira spp. and to determine the prevalence of pathogenic leptospires at recreational areas in Peninsular Malaysia. Soil and water samples were randomly collected from 33 recreational areas in Peninsular Malaysia from December 2018 to April 2019. Each culture was examined under dark-field microscopy prior to genus confirmation by polymerase chain reaction using primers for the 16S rRNA gene. A total of 390 water and soil samples were collected, and 131 cultures were positive for Leptospira under dark-field microscope examination. Leptospira was identified in most of the recreational areas sampled, and at least one pathogenic Leptospira species was isolated from 17 recreational areas. The prevalence of saprophytic, intermediate, and pathogenic Leptospira spp. was 19.7%, 5.6%, and 8.2%, respectively. The dominant pathogenic species found in the samples was Leptospira kmetyi. This study provides important data on the distribution and prevalence of Leptospira spp. from soil and water, as well as the dominant pathogenic species, at recreational areas in Peninsular Malaysia. Therefore, preventive measures should be taken to ensure the safety of visitors.

Declining malaria parasite prevalence and trends of asymptomatic parasitaemia in a seasonal transmission setting in North-Western Burkina Faso between 2000 and 2009-2012.

BACKGROUND: Malaria transmission was reported to have declined in some East African countries. However, a comparable trend has not been confirmed for West Africa. This study aims to assess the dynamics of parasite prevalence and malaria species distribution over time in an area of highly seasonal transmission in Burkina Faso. The aim was also to compare frequency of asymptomatic parasitaemia between wet and dry season by parasite density status and age group. METHODS: During the years 2009-2012, six cross-sectional studies were performed in the rural village Bourasso in the Nouna Health District in north-west Burkina Faso. In subsequent rainy and dry seasons blood samples were collected to assess the parasite prevalence, species, density and clinical parameters. In total, 1,767 children and adults were examined and compared to a baseline collected in 2000. RESULTS: The microscopical parasite prevalence (mainly P. falciparum) measured over the rainy seasons decreased significantly from 78.9% (2000) to 58.4%, 55.9% and 49.3%, respectively (2009-2011; p <0.001). The frequency of Plasmodium malariae infections (mono- and co-infections) decreased parallel to the overall parasite prevalence from 13.4% in 2000 to 2.1%, 4.1% and 4.7% in 2009-2011 (p <0.001). Comparing parasite-positive subjects from the rainy season versus dry season, the risk of fever was significantly reduced in the dry season adjusting for parasite density (grouped) and age group. CONCLUSIONS: The results of this study suggest a decline of malaria transmission over the rainy seasons between 2000 and 2009-2011 in the region of Nouna, Burkina Faso. The decreased transmission intensity was associated with lower prevalence of P. malariae infections (both mono-infections and co-infections). Asymptomatic parasitaemia was more frequent in the dry season even adjusting for parasite density and age group in a multivariate regression. Possible reasons for this observation include the existence of less pathogenic Plasmodium falciparum genotypes prevailing in the dry season, or the effect of a reduced incidence density during the dry season.