Recently, P218, a new flexible antifolate targeting Plasmodium falciparum dihydrofolate reductase (PfDHFR), has entered its clinical trial with good safety profile and effective Pf infection prevention. However, it carries a free carboxyl terminal, which is hydrophilic and prone to metabolic glucuronidation. Here, a new series of P218 analogues carrying butyrolactone has been synthesized with the purpose of enhancing lipophilicity and minimizing metabolic instability. The inhibition constants against the mutant PfDHFR enzymes are in sub-nanomolar level and the antimalarial activity against antifolate-resistant parasites are in the low micromolar range. The crystal structure of the most potent analogue LA1 bound enzyme complex indicates interaction with multiple residues, including Arg122 and Phe116 in the active site. In vitro log D7.4 and kinetic solubility confirmed a higher lipophilicity of this butyrolactone series as compared to P218. These outcomes suggest the possibility to further develop butyrolactone derivatives as non-carboxyl antiplasmodial antifolates.

Aim: To assess the functional relevance of a putative Major Facilitator Superfamily protein (PF3D7_0210300; \'PfMFSDT\') as a drug transporter, using Candida glabrata for orthologous protein expression.Methods: Complementary Determining Sequence encoding PfMFSDT was integrated into the genome of genetically engineered C. glabrata strain MSY8 via homologous recombination, followed by assessing its functional relevance as a drug transporter.Results & conclusion: The modified C. glabrata strain exhibited plasma membrane localization of PfMFSDT and characteristics of an Major Facilitator Superfamily transporter, conferring resistance to antifungals, ketoconazole and itraconazole. The nanomolar inhibitory effects of the drugs on the intra-erythrocytic growth of Plasmodium falciparum highlight their antimalarial properties. This study proposes PfMFSDT as a drug transporter, expanding the repertoire of the currently known antimalarial \'resistome\'.
[Box: see text].

Primaquine (PQ) is a widely used antimalarial drug, but its high dosage requirements can lead to significant tissue damage and adverse gastrointestinal and hematological effects. Recent studies have shown that nanoformulations can enhance the bioavailability of pharmaceuticals, thereby increasing efficacy, reducing dosing frequency, and minimizing toxicity. In this study, PQ-loaded PLGA nanoparticles (PQ-NPs) were prepared using a modified double emulsion solvent evaporation technique (w/o/w). The PQ-NPs exhibited a mean particle size of 228 ± 2.6 nm, a zeta potential of +27.4 mV, and an encapsulation efficiency of 81.3 ± 3.5%. Scanning electron microscopy (SEM) confirmed their spherical morphology, and the in vitro release profile demonstrated continuous drug release over 72 h. Differential scanning calorimetry (DSC) thermograms indicated that the drug was present in the nanoparticles, with improved physical stability. Fourier-transform infrared spectroscopy (FTIR) analysis showed no interactions between the various substances in the NPs. In vivo studies in Swiss albino mice infected with Plasmodium berghei revealed that the nanoformulated PQ was 20% more effective than the standard oral dose. Biodistribution studies indicated that 80% of the NPs accumulated in the liver, highlighting their potential for targeted drug delivery. This research demonstrates the successful development of a nanomedicine delivery system for antimalarial drugs, offering a promising strategy to enhance treatment efficacy while reducing adverse effects.

While the use of plants in traditional medicine dates back to 1500 B.C., modern advancements led to the development of innovative therapeutic techniques. On the other hand, in the field of anti-infective agents, lack of efficacy and the onset of resistance stimulate the search for novel agents. Genus Artemisia is one of the most diverse among perennial plants with a variety of species, properties, and chemical components. The genus is known for its therapeutic values and, in particular, for its role in the origin of antimalarial agents derived from artemisinin. In this review, we aim to provide an updated overview of the evolution of natural and natureinspired compounds related to the genus Artemisia that have been proven, in vitro and in vivo, to possess antimalarial properties. An overview of the chemical composition and a description of the ethnopharmacological aspects will be presented, as well as an updated report on in vitro and in vivo evidence that allowed the translation of artemisinin and its derivatives from traditional chemistry into modern medicinal chemistry. The biological and structural properties will be discussed, also dedicating attention to the challenging tasks that still are open, such as the identification of optimal combination strategies, the routes of administration, and the full assessment of the mechanism of action.

Antimalarial resistance in Plasmodium falciparum is a public health problem in the fight against malaria in Ecuador. Characterizing the molecular epidemiology of drug resistance genes helps to understand the emergence and spread of resistant parasites. In this study, the effects of drug pressure and human migration on antimalarial resistance in P. falciparum were evaluated. Sixty-seven samples from northwestern Ecuador from the 2019-2021 period were analyzed. SNPs in Pfcrt , Pfdhps , Pfdhfr , Pfmdr-1 , Pfk13 and Pfaat1 were identified by Sanger sequencing and whole-genome sequencing. A comparison of the frequencies of the haplotypes was made with data from the 2013-2015 period. Also, nucleotide and haplotype diversity were calculated. The frequencies of the mutant haplotypes, CVM ET in Pfcrt and C I C N I in Pfdhfr , increased. NED F S D F Y in Pfmdr-1 was detected for the first time. While the wild-type haplotypes, SAKAA in Pfdhps and MYRIC in Pfk13 , remained dominant. Interestingly, the A16 V mutation in Pfdhfr that gives resistance to proguanil is reported in Ecuador. In conclusion, parasites resistant to chloroquine ( Pfcrt ) and pyrimethamine ( Pfdhfr ) increased in recent years, while parasites sensitive to sulfadoxine ( Pfdhps ) and artemisinin ( Pfk13 ) prevail in Ecuador. Therefore, the current treatment is still useful against P. falciparum . The frequent human migration between Ecuador and Colombia has likely contributed to the spread of resistant parasites. Keys words : Plasmodium falciparum , resistance, antimalarial, selective pressure, human migration.

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC50) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

The rise of multidrug-resistant malaria requires accelerated development of novel antimalarial drugs. Pharmacokinetic-pharmacodynamic (PK-PD) models relate blood antimalarial drug concentrations with the parasite-time profile to inform dosing regimens. We performed a simulation study to assess the utility of a Bayesian hierarchical mechanistic PK-PD model for predicting parasite-time profiles for a Phase 2 study of a new antimalarial drug, cipargamin. We simulated cipargamin concentration- and malaria parasite-profiles based on a Phase 2 study of eight volunteers who received cipargamin 7 days after inoculation with malaria parasites. The cipargamin profiles were generated from a two-compartment PK model and parasite profiles from a previously published biologically informed PD model. One thousand PK-PD data sets of eight patients were simulated, following the sampling intervals of the Phase 2 study. The mechanistic PK-PD model was incorporated in a Bayesian hierarchical framework, and the parameters were estimated. Population PK model parameters describing absorption, distribution, and clearance were estimated with minimal bias (mean relative bias ranged from 1.7% to 8.4%). The PD model was fitted to the parasitaemia profiles in each simulated data set using the estimated PK parameters. Posterior predictive checks demonstrate that our PK-PD model adequately captures the simulated PD profiles. The bias of the estimated population average PD parameters was low-moderate in magnitude. This simulation study demonstrates the viability of our PK-PD model to predict parasitological outcomes in Phase 2 volunteer infection studies. This work will inform the dose-effect relationship of cipargamin, guiding decisions on dosing regimens to be evaluated in Phase 3 trials.

Cytochrome P450 3A4 (CYP3A4) enzyme is involved in the metabolism of about 30 % of clinically used drugs, including the antimalarials artemether and lumefantrine. CYP3A4 polymorphisms yield enzymatic variants that contribute to inter-individual variation in drug metabolism. Here, we examined CYP3A4 polymorphisms in populations from malaria-endemic islands in Lake Victoria, Kenya, and Vanuatu, to expand on the limited data sets. We used archived dried blood spots collected from 142 Kenyan and 263 ni-Vanuatu adults during cross-sectional malaria surveys in 2013 and 2005-13, respectively, to detect CYP3A4 variation by polymerase chain reaction (PCR) and sequencing. In Kenya, we identified 14 CYP3A4 single nucleotide polymorphisms (SNPs), including the 4713G (CYP3A4∗1B; allele frequency 83.9 %) and 19382A (CYP3A4∗15; 0.7 %) variants that were previously linked to altered metabolism of antimalarials. In Vanuatu, we detected 15 SNPs, including the 4713A (CYP3A4∗1A; 88.6 %) and 25183C (CYP3A4∗18; 0.6 %) variants. Additionally, we detected a rare and novel SNP C4614T (0.8 %) in the 5\' untranslated region. A higher proportion of CYP3A4 genetic variance was found among ni-Vanuatu populations (16 %) than among Lake Victoria Kenyan populations (8 %). Our work augments the scarce data sets and contributes to improved precision medicine approaches, particularly to anti-malarial chemotherapy, in East African and Pacific Islander populations.

BACKGROUND: There is a dearth of studies investigating the efficacy of hydroxychloroquine in the treatment of either anogenital lichen sclerosus or extragenital lichen sclerosus, a condition that, if left untreated, could lead to a greater degree of scarring and malignant transformation.
OBJECTIVE: This study aims to analyze the demographic characteristics, clinicopathological features, treatment response, and outcomes of patients diagnosed with either anogenital or extragenital lichen sclerosus who received hydroxychloroquine therapy.
METHODS: A retrospective analysis was conducted involving 70 patients diagnosed with lichen sclerosus who underwent treatment with hydroxychloroquine at our institution between 2018 and 2023.
RESULTS: Among the cohort, 67 patients were female, and 3 were male. Extragenital lichen sclerosus was diagnosed in 23 patients, with 16 exhibiting concomitant morphea overlap. Itching was the predominant clinical presentation (67%). A notable proportion of patients (36%) had a connective tissue disorder, prompting hydroxychloroquine therapy. Among the 30 patients treated solely for lichen sclerosus, 21 demonstrated response and 9 had no response. From a broader comparison of response to hydroxychloroquine, the overall anogenital response rate was 84.6% as opposed to 50% in extragenital lichen sclerosus. The median time to initial response was 4 months. Adverse effects, predominantly mild, were observed in 10 (14.3%) patients.
CONCLUSIONS: This study is constrained by its retrospective nature and reliance on data from a single center, resulting in a limited sample size.
CONCLUSIONS: Hydroxychloroquine demonstrates promise as a therapeutic option for anogenital lichen sclerosus because of its favorable response rates and low incidence of adverse effects. However, further investigations, including larger-scale or prospective studies, are imperative to ascertain its definitive efficacy.

Emerging resistance to current antimalarials is reducing their effectiveness and therefore there is a need to develop new antimalarial therapies. Toward this goal, high throughput screens against the P. falciparum asexual parasite identified the pyrazolopyridine 4-carboxamide scaffold. Structure-activity relationship analysis of this chemotype defined that the N1-tert-butyl group and aliphatic foliage in the 3- and 6-positions were necessary for activity, while the inclusion of a 7\'-aza-benzomorpholine on the 4-carboxamide motif resulted in potent anti-parasitic activity and increased aqueous solubility. A previous report that resistance to the pyrazolopyridine class is associated with the ABCI3 transporter was confirmed, with pyrazolopyridine 4-carboxamides showing an increase in potency against parasites when the ABCI3 transporter was knocked down. The low metabolic stability intrinsic to the pyrazolopyridine scaffold and the slow rate by which the compounds kill asexual parasites resulted in poor performance in a P. berghei asexual blood stage mouse model. Lowering the risk of resistance and mitigating the metabolic stability and cytochrome P450 inhibition will be challenges in the future development of the pyrazolopyrimidine antimalarial class.