Parasitic Resistance Research Articles

<i>In-Silico</i> Screening of Prenylated Quercetin from <i>Globimetula oreophila</i> Against <i>Plasmodium falciparum</i> Enzymes: Hope for New Antimalarial Drugs

Malaria continues to be one of the most devastating global health problems due to the high morbidity and mortality it causes in endemic regions. The search for new antimalarial targets is vital because of the increasing prevalence of drug resistance in malaria parasites. Malarial proteases constitute promising therapeutic targets as they play important roles in the parasite life cycle. The inhibition of these enzymes has pharmacological and therapeutic significance since they are involved in numerous processes, including the development, invasion, egress, and breakdown of host hemoglobin to release amino acids for parasite sustenance. In this study, <i>in silico</i> techniques were used to shed light on the mechanisms underlying the inhibitory effects of prenylated quercetin isolated from <i>Globimetula oreophila</i> on plasmepsin I and II, falciparum 2 and 3, <i>Plasmodium falciparum</i> calcium-dependent protein kinase 2, dihydrofolate reductase-thymidylate synthase, and serine repeat antigen 5. The test compound significantly interacts with key enzyme binding pockets through hydrogen bonds, van der Waals, and hydrophobic interactions, influencing protease specificity control. Crucial ligand features like carbonyl and hydroxyl groups were identified as essential for receptor interactions. Comparative analysis revealed the test compound's strong binding affinities with energies ranging from -6.4 Kcal/mol to -9.4 Kcal/mol, indicating competitive potential against various enzymes, particularly excelling against <i>Pf</i>DHFR-TS, plasmepsin-I, and SERA5 compared to native ligands. This suggests the compound's ability to competitively inhibit enzyme activity by targeting co-factor binding sites, especially with specific proteases, holding promise for therapeutic applications as potent inhibitors for the prevention and treatment of malaria.

Comprehensive evaluation of recombination confined performance of CuGaO2 for solar cell application

In the quest to find an outstanding solar energy capturing system that meets requirements like affordability, widespread availability, eco-friendliness, remarkable efficiency, and enduring stability, thorough investigations have been carried out to explore the possibilities presented by ‘Delafossite’ copper gallium oxide (CuGaO2). β-CuGaO2 has an ideal bandgap of 1.5 eV, along with a high absorption coefficient and excellent carrier mobility, making it well-suited for high-efficiency solar cell applications. Theoretical modelling, utilizing the optical and electrical attributes of the CuGaO2 (CGO) material, is employed to analyze its photovoltaic performance when used as an absorber. The detailed balance analysis showed 56.9% of the incident power is wasted in spectrum loss (as thermalisation and non-absorption loss), 10.1% is wasted in intrinsic losses (such as radiative recombination, radiation dilution, entropy generation etc,), extrinsic recombination (originating from electrical losses, parasitic resistance, finite mobility, surface recombination velocity (SRV), non-ohmic contacts etc), eats up another 9.5% and the resultant 23.6% is available as net useful efficiency. Through the careful selection of a suitable buffer counterpart and optimization of material parameters, absorber thickness, defect density, contacts, and SRV, the CGO device dem onstrates an efficiency of 23.6%.

Global Fight against Malaria: Goals and Achievements 1900–2022

This article examines the historical and ongoing efforts to fight malaria, a parasitic disease caused by Plasmodium species and transmitted by Anopheles mosquitoes. Despite over a century of control efforts, malaria remains a major global health issue. In 2022, there were an estimated 249 million cases across 85 countries, leading to approximately 600,000 deaths. In the recently published Global Technical Strategy for Malaria 2016–2030, the World Health Organization (WHO) has prioritized malaria eradication. The main goals are to reduce malaria incidence and mortality by 90% by 2030 compared to 2015 levels. However, as of 2022, progress has been limited, with only a 2% reduction in incidence and a 6% reduction in mortality. This review traces the historical context of malaria, highlighting its ancient origins and the pivotal scientific discoveries in the late 19th century that paved the way for modern control measures. The Global Malaria Eradication Programme launched by the WHO in 1955 initially showed promise, largely due to the insecticide DDT, but ultimately failed to achieve its goals mainly due to logistical problems, vector resistance to DDT, and inadequate funding. Despite significant advances in the early 21st century, including the Roll Back Malaria initiative and increased international funding, malaria eradication remains a distant goal. Persistent challenges, such as weak healthcare systems, parasite and vector resistance to drugs and insecticides, and inadequate funding, continue to hamper global efforts. Therefore, this article underscores the need for a deeper understanding of malaria’s history and recent evolution to inform future strategies for eradication.

Evaluating the potential of non-immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies.

Toxoplasmosis persists as a prevalent disease, facing challenges from parasite resistance and treatment side effects. Consequently, identifying new drugs by exploring novel protein targets is essential for effective intervention. Cyclosporin A (CsA) possesses antiparasitic activity against Toxoplasma gondii, with cyclophilins identified as possible targets. However, CsA immunosuppressive nature hinders its use as an antitoxoplasmosis agent. Here, we evaluate the potential of three CsA derivatives devoid of immunosuppressive activity, namely, NIM811, Alisporivir, and dihydrocyclosporin A to target a previously characterized cyclophilin from Toxoplasma gondii (TgCyp23). We determined the X-ray crystal structures of TgCyp23 in complex with the three analogs and elucidated their binding and inhibitory properties. The high resolution of the structures revealed the precise positioning of ligands within the TgCyp23 binding site and the details of protein-ligand interactions. A comparison with the established ternary structure involving calcineurin indicates that substitutions at position 4 in CsA derivatives prevent calcineurin binding. This finding provides a molecular explanation for why CsA analogs can target Toxoplasma cyclophilins without compromising the human immune response.

In artemisinin-resistant falciparum malaria parasites, mitochondrial metabolic pathways are essential for survival but not those of apicoplast

Emergence and spread of parasite resistance to artemisinins, the first-line antimalarial therapy, threaten the malaria eradication policy. To identify therapeutic targets to eliminate artemisinin-resistant parasites, the functioning of the apicoplast and the mitochondrion was studied, focusing on the fatty acid synthesis type II (FASII) pathway in the apicoplast and the electron transfer chain in the mitochondrion. A significant enrichment of the FASII pathway among the up-regulated genes in artemisinin-resistant parasites under dihydroartemisinin treatment was found, in agreement with published transcriptomic data. However, using GC-MS analyzes of fatty acids, we demonstrated for the first time that the FASII pathway is non-functional, ruling out the use of FASII inhibitors to target artemisinin-resistant parasites. Conversely, by assessing the modulation of the oxygen consumption rate, we evidenced that mitochondrial respiration remains functional and flexible in artemisinin-resistant parasites and even at the quiescent stage. Two novel compounds targeting electron transport chain (ELQ300, ELQ400) efficiently killed quiescent artemisinin-resistant parasites. Therefore, mitochondrial respiration represents a key target for the elimination of artemisinin-resistant persistent Plasmodium falciparum parasites.

A combination of four Toxoplasma gondii nuclear-targeted effectors protects against interferon gamma-driven human host cell death.

In both mice and humans, Type II interferon gamma (IFNγ) is crucial for the regulation of Toxoplasma gondii (T. gondii) infection, during acute or chronic phases. To thwart this defense, T. gondii secretes protein effectors hindering the host's immune response. For example, T. gondii relies on the MYR translocon complex to deploy soluble dense granule effectors (GRAs) into the host cell cytosol or nucleus. Recent genome-wide loss-of-function screens in IFNγ-primed primary human fibroblasts identified MYR translocon components as crucial for parasite resistance against IFNγ-driven vacuole clearance. However, these screens did not pinpoint specific MYR-dependent GRA proteins responsible for IFNγ signaling blockade, suggesting potential functional redundancy. Our study reveals that T. gondii depends on the MYR translocon complex to prevent parasite premature egress and host cell death in human cells stimulated with IFNγ post-infection, a unique phenotype observed in various human cell lines but not in murine cells. Intriguingly, inhibiting parasite egress did not prevent host cell death, indicating this mechanism is distinct from those described previously. Genome-wide loss-of-function screens uncovered TgIST, GRA16, GRA24, and GRA28 as effectors necessary for a complete block of IFNγ response. GRA24 and GRA28 directly influenced IFNγ-driven transcription, GRA24's action depended on its interaction with p38 MAPK, while GRA28 disrupted histone acetyltransferase activity of CBP/p300. Given the intricate nature of the immune response to T. gondii, it appears that the parasite has evolved equally elaborate mechanisms to subvert IFNγ signaling, extending beyond direct interference with the JAK/STAT1 pathway, to encompass other signaling pathways as well.IMPORTANCEToxoplasma gondii, an intracellular parasite, affects nearly one-third of the global human population, posing significant risks for immunocompromised patients and infants infected in utero. In murine models, the core mechanisms of IFNγ-mediated immunity against T. gondii are consistently preserved, showcasing a remarkable conservation of immune defense mechanisms. In humans, the recognized restriction mechanisms vary among cell types, lacking a universally applicable mechanism. This difference underscores a significant variation in the genes employed by T. gondii to shield itself against the IFNγ response in human vs murine cells. Here, we identified a specific combination of four parasite-secreted effectors deployed into the host cell nucleus, disrupting IFNγ signaling. This disruption is crucial in preventing premature egress of the parasite and host cell death. Notably, this phenotype is exclusive to human cells, highlighting the intricate and unique mechanisms T. gondii employs to modulate host responses in the human cellular environment.

Influence of the Bias Voltage on Effective Electron Velocity in AlGaN/GaN High Electron Mobility Transistors.

The small-signal S parameters of the fabricated double-finger gate AlGaN/GaN high electron mobility transistors (HEMTs) were measured at various direct current quiescent operating points (DCQOPs). Under active bias conditions, small-signal equivalent circuit (SSEC) parameters such as Rs and Rd, and intrinsic parameters were extracted. Utilizing fT and the SSEC parameters, the effective electron velocity (νe-eff) and intrinsic electron velocity (νe-int) corresponding to each gate bias (VGS) were obtained. Under active bias conditions, the influence mechanism of VGS on νe-eff was systematically studied, and an expression was established that correlates νe-eff, νe-int, and bias-dependent parasitic resistances. Through the analysis of the main scattering mechanisms in AlGaN/GaN HEMTs, it has been discovered that the impact of VGS on νe-eff should be comprehensively analyzed from the aspects of νe-int and parasitic resistances. On the one hand, changes in VGS influence the intensity of polar optical phonon (POP) scattering and polarization Coulomb field (PCF) scattering, which lead to changes in νe-int dependent on VGS. The trend of νe-int with changes in VGS plays a dominant role in determining the trend of νe-eff with changes in VGS. On the other hand, both POP scattering and PCF scattering affect νe-eff through their impact on parasitic resistance. Since there is a difference in the additional scattering potential corresponding to the additional polarization charges (APC) between the gate-source/drain regions and the region under the gate, the mutual effects of PCF scattering on the under-gate electron system and the gate-source/drain electron system should be considered when adjusting the PCF scattering intensity through device structure optimization to improve linearity. This study contributes to a new understanding of the electron transport mechanisms in AlGaN/GaN HEMTs and provides a novel theoretical basis for improving device performance.

Simulation study of cadmium-free CIGS solar cell for efficiency enhancement by minimizing recombination losses through back surface field mechanism

Thin-film photovoltaic cells provide benefits over conventional first-generation technology, including lighter weight, greater flexibility, and lower power generation costs. Chalcogenide solar cells offer good efficiency and technological maturity among thin-film technology. In this work, a solar cell device structure, Al/FTO/SnS2/CIGS/CuO/Ni, is examined using SCAPS-1D. Further, by incorporating the back surface field (BSF) layer, the conversion efficiency increased from 18.93 % to 29.88 %, followed by VOC of 0.96 V, JSC of 37.07 mA cm−2, and FF of 83.71 %. This increment in device performance is owing to the lowering back surface recombination velocity and the additional hole tunnelling activity offered by the BSF layer by forming a quasi-ohmic contact, i.e. metal-semiconductor contact with negligible junction resistance relative to the total resistance of the device. Throughout this research work, the authors studied several factors such as surface recombination velocity, temperature impact, front and back contact metal work functions, parasitic resistance impact, gallium proportion, and doping density impact on CIGS solar cells. The work also included a calibration with experimental data from published sources to validate the simulation results.This paper presents a new approach for producing high-efficiency, eco-friendly CIGS solar cells with CuO back surface field mechanism.

A high content imaging assay for identification of specific inhibitors of native Plasmodium liver stage protein synthesis.

Plasmodium parasite resistance to antimalarial drugs is a serious threat to public health in malaria-endemic areas. Compounds that target core cellular processes like translation are highly desirable, as they should be capable of killing parasites in their liver and blood stage forms, regardless of molecular target or mechanism. Assays that can identify these compounds are thus needed. Recently, specific quantification of native Plasmodium berghei liver stage protein synthesis, as well as that of the hepatoma cells supporting parasite growth, was achieved via automated confocal feedback microscopy of the o-propargyl puromycin (OPP)-labeled nascent proteome, but this imaging modality is limited in throughput. Here, we developed and validated a miniaturized high content imaging (HCI) version of the OPP assay that increases throughput, before deploying this approach to screen the Pathogen Box. We identified only two hits; both of which are parasite-specific quinoline-4-carboxamides, and analogs of the clinical candidate and known inhibitor of blood and liver stage protein synthesis, DDD107498/cabamiquine. We further show that these compounds have strikingly distinct relationships between their antiplasmodial and translation inhibition efficacies. These results demonstrate the utility and reliability of the P. berghei liver stage OPP HCI assay for the specific, single-well quantification of Plasmodium and human protein synthesis in the native cellular context, allowing the identification of selective Plasmodium translation inhibitors with the highest potential for multistage activity.

Performance optimization of a novel perovskite solar cell with power conversion efficiency exceeding 37% based on methylammonium tin iodide

The development of highly efficient lead-free solar cells is essential for sustainable energy production in the face of depleting fossil fuel resources and the negative effects of climate change. Perovskite solar cells (PSCs) containing lead pose considerable environmental and public health hazards, in addition to thermal stability and longevity challenges. Here, a novel lead-free solar cell design of the configuration, ITO/PC61BM/CH3NH3SnI3/PEDOT:PSS/Mo, is investigated for improved light harvesting capabilities, enhanced device performance, and better operational efficiency under various temperature conditions. The optimal thickness of the light-absorbing layer, CH3NH3SnI3, was found to be 1000 nm for maximum quantum efficiency (QE). Further, the temperature tolerance of the solar cell was evaluated using Mott-Schottky (MS) capacitance analysis and showed that the model cell retains about 95% of its power at 400 K, demonstrating excellent thermal stability and robust performance. The solar cell also shows promising electrical output parameters, including a short-circuit current density (Jsc) of 34.84 mA/cm², open-circuit voltage (Voc) of 1.5226 V, Fill factor (FF) of 71.04%, and an impressive power conversion efficiency (PCE) of 37.66% at 300 K. The effect of buffer layers such as CdS, ZnS, ZnSe, and V2O5 on the electrical outcomes of the model cell structure has been critically examined. Additionally, parasitic resistances and doping characteristics on the operational performance of the cell have been explored in detail. This work therefore, provides remarkable insights in the field of solar energy harvesting, offering potential sustainable energy generation solutions, supporting de-carbonization of the environment and climate change mitigation efforts towards an energy sustainable future.

Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data

The selection and combination of dose regimens for antimalarials involve complex considerations including pharmacokinetic and pharmacodynamic interactions. In this study, we use immediate ex vivo P. falciparum field isolates to evaluate the effect of cabamiquine and pyronaridine as standalone treatments and in combination therapy. We feed the data into a pharmacometrics model to generate an interaction map and simulate meaningful clinical dose ratios. We demonstrate that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development.

Antimalarial drug sulfadoxine induces gametocytogenesis in Plasmodium berghei

BackgroundThe spread of antimalarial drug resistance parasites is a major obstacle in eliminating malaria in endemic areas. This increases the urgency for developing novel antimalarial drugs with improved profiles to eliminate both sensitive and resistant parasites in populations. The invention of the drug candidates needs a model for sensitive and resistant parasites on a laboratory scale.MethodsRepeated Incomplete Treatment (RIcT) method was followed in raising the rodent malaria parasite, Plasmodium berghei, resistant to sulfadoxine. Plasmodium berghei were exposed to an adequate therapeutic dose of sulfadoxine without finishing the treatment to let the parasite recover. Cycles of drug treatment and parasite recovery were repeated until phenotypic resistance appeared.ResultsAfter undergoing 3–4 cycles, phenotypic resistance was not yet found in mice treated with sulfadoxine. Nevertheless, the molecular biology of dhps gene (the target of sulfadoxine) was analyzed at the end of the RIcT cycle. There was no mutations found in the gene target. Interestingly, the appearance of gametocytes at the end of every cycle of drug treatment and parasite recovery was observed. These gametocytes later on would no longer extend their life in the RBC stage, unless mosquitoes bite the infected host. This phenomenon is similar to the case in human malaria infections treated with sulfadoxine-pyrimethamine (SP).ConclusionsIn this study, the antimalarial drug sulfadoxine induced gametocytogenesis in P. berghei, which could raise the risk factor for malaria transmission.

Influence of the magnetic field on the shunt resistance of an n+p-p+ silicon solar cell in the frequency modulation

A photovoltaic cell is a device that generates electricity directly from visible light. Several factors affect the conversion efficiency of solar cells. Parasitic resistances such as the shunt resistance is a fundamental parameter of the equivalent electrical model of the solar cell, which induces the leakage current of electrical charges when its value is low. It represents all leakage currents within the solar cell. It is also an indicator of good or poor quality of a solar cell, since a high value indicates low leakage current through the cell, and vice versa. A number of measurement techniques are used to determine the leakage current, in particular electrical current and voltage.

In vitro evaluation of ganaplacide/lumefantrine combination against Plasmodium falciparum in a context of artemisinin resistance.

Ganaplacide, also known as KAF156, is among the new antimalarial drug candidates that have successfully reached Phase III clinical trials, and is proposed in combination with lumefantrine. This combination could replace the current front-line artemisinin-based combination therapies (ACTs) in case of Plasmodium falciparum resistance to both artemisinins and partner drugs. Indeed, the African continent, where the malaria burden is the highest, is currently experiencing worrying multiple emergences and spread of artemisinin resistance, which urges for the exploration of the antiparasitic properties of KAF156 in this context. The objectives of this work were firstly to evaluate the risk of cross-resistance between artemisinins and KAF156 alone, and in combination with lumefantrine, using a panel of artemisinin-resistant strains carrying different pfk13 mutations and markers of other antiplasmodial drug resistances; secondly to explore in vitro the relevance of combining KAF156 and lumefantrine with artemisinins, based on the model of triple ACTs. Our results highlighted that KAF156 activity was not impaired by mutations in pfk13, pfcrt, pfmdr1, pfmdr2, pfdhps and pfdhfr genes or by pfmdr1 amplification. Moreover, we demonstrated that KAF156 alone and in combination with lumefantrine was active against artemisinin-resistant parasites, including when they are quiescent. All these in vitro results evidence that multi-drug resistant parasites currently in circulation in the field might not affect KAF156 efficacy, and are encouraging signs for KAF156 use in a triple ACT to preserve the use of artemisinins for as long as possible.

A tradeoff between bacteriophage resistance and bacterial motility is mediated by the Rcs phosphorelay in Escherichia coli.

Across the tree of life, pleiotropy is thought to constrain adaptation through evolutionary tradeoffs. However, few examples of pleiotropy exist that are well explained at the genetic level, especially for pleiotropy that is mediated by multiple genes. Here, we describe a set of pleiotropic mutations that mediate two key fitness components in bacteria: parasite resistance and motility. We subjected Escherichia coli to strong selection by phage U136B to obtain 27 independent mucoid mutants. Mucoidy is a phenotype that results from excess exopolysaccharide and can act as a barrier against viral infection but can also interfere with other cellular functions. We quantified the mutants' phage resistance using efficiency of plaquing assays and swimming motility using swim agar plates, and we sequenced the complete genomes of all mutants to identify mucoid-causing mutations. Increased phage resistance co-occurred with decreased motility. This relationship was mediated by highly parallel (27/27) mutations to the Rcs phosphorelay pathway, which senses membrane stress to regulate exopolysaccharide production. Together, these results provide an empirical example of a pleiotropic relationship between two traits with intermediate genetic complexity.

Hourglass transistor: An alternative and improved MOS structure robust to total ionization dose radiation

This paper presents a novel MOSFET layout named the “hourglass transistor”, aimed to improve its electrical behavior under Total Ionizing Dose (TID) effects. The new radiation-tolerant device is based on augmenting parasitic channel resistance, alteration of the electric field by the longitudinal corner effect (LCE), and reducing channel resistance within the central gate region. The radiation-robust MOS structure design was implemented in a 130 nm CMOS bulk process and its performance was analyzed through simulations using 3D physical models. The proposed hourglass transistor was compared with rectangular, diamond, dog bone and H-gate devices, showing a reduction in the post-radiation Ioff current of 8.77, 4.6, 1.85 and 13.7 times, respectively; and a pre-radiation normalized saturation current of 2.29, 1.04, 1.58 and 1.52 times greater with an increase of 4.84, 1, 2.47 and 2.03 times the gate area, respectively.

Advancements in CIGS/ZnS heterojunction solar cells: Experimental and numerical analysis

This study presents a comprehensive experimental investigation conducted on a CIGS-based solar cell incorporating a ZnS buffer layer. The primary objective was to determine key parameters of the CIGS/ZnS heterojunction, including parasitic resistances (Rs and Rsh), ideality factor (n), and barrier height (ϕB), using experimental current-voltage (I-V) characteristics over a temperature range of 150 K to 300 K under dark conditions. The heterojunction was modelled using a single-diode electrical circuit that accounted for parasitic resistances. Two methods were employed for parameter determination: direct analysis of the (I-V) curves and Cheung's method. Additionally, the charge transport mechanism within the heterojunction is investigated and discussed. Furthermore, the performance of the Al:ZnO/i:ZnO/ZnS/CIGS/Mo solar cell was assessed using the SCAPS-1D simulator, demonstrating an initial solar energy conversion efficiency of 15.01 %. To enhance this efficiency, a hole transport layer (HTL) was integrated between the back electrode and the absorber layer. Extensive studies were conducted to optimize the thickness and doping density of the HTL, including a comparative analysis of different materials used as HTLs. These optimizations resulted in a significant increase in conversion efficiency, reaching up to 28.68 %.

A new hybrid fixed and adaptive gains control algorithm to reduce power losses on LLCL filter-based renewable energy conversion systems with systematic parametrization using Grey Wolf optimizer

Currently, there is a transition in the energy matrix around the world, where traditional sources of energy generation are continually being replaced by energy generation systems based on renewable sources to mitigate the climate crisis. In this bias, this work presents the mathematical modeling of an LLCL filter, used to connect power generation systems based on renewable energy sources to the electrical grid, and presents a novel hybrid fixed-and adaptive gains control strategy for current injection into the grid using this system. The developed hybrid controller is composed of a proportional–integral controller and a direct robust adaptive controller. The first term of the controller guarantees the reference current, while the second term of the controller is used for disturbance rejection. Furthermore, a systematic procedure for the controller’s parametrization based on Grey Wolf Optimizer is also provided. The control of the current injected into the grid is carried out considering the LLCL filter without passive damping resistors in the filter structure to avoid power losses due to the passive filter elements. Additionally, the LLCL filter model considers minimal parasitic resistances to evaluate the controller’s performance and optimize it for the application of interest, aiming to maximize the system performance by ensuring a short transient regime due to the fast closed-loop system response. Simulation results indicate high performance of this optimized control strategy with small tracking error even considering grid impedance variations.

Novel Diacyl-hydrazide Compounds as Potential Therapeutics for Visceral Leishmaniasis.

Visceral leishmaniasis is a neglected tropical disease with the highest mortality among different forms of leishmaniasis manifestation in humans. The disease is caused by the parasitic protists Leishmania donovani and Leishmania infantum, and treatments remain unsuitable due to high costs, complicated administration, lack of efficacy, variable patient susceptibility, toxic side effects, and rising parasitic resistance. Herein, we report a structure-activity relationship (SAR) exploration of the diacyl-hydrazide scaffold identified to have antiparasitic activity from a high-throughput screen against L. donovani, Trypanosoma cruzi, and Trypanosoma brucei. This SAR study revealed new structural insights into this scaffold related to bioactivity resulting in a new series of lead compounds with nanomolar activity against L. donovani and no toxicity against human THP-1 macrophages. These optimized diacyl-hydrazide compounds set the stage for future drug development and hold promise for a new treatment avenue for visceral leishmaniasis.

Antiparasitic Effects of Niosomal Formulations of Curcumin and Silymarin Against Toxoplasma gondii In Vitro.

Background: Toxoplasmosis is caused by infection with Toxoplasma gondii. No Symptoms in healthy people. Notably, very dangerous symptoms in immunocompromised, or patients with immune diseases. Previous research has shown that the parasite's resistance to drugs continues to emerge and has indicated this resistance as a cause for concern. In this context, researchers have a great responsibility to search for alternative treatments, as well as to develop existing ones. Essentially, this improves the therapeutic efficacy of drugs and prevents the emergence of resistance to them. The present study aims to evaluate antitoxoplasma effects of niosomal loaded curcumin and silymarin and their synergistic effects with clindamycin against T. gondii RH strain in vitro. Materials and Methods: Experiments were conducted on the tachyzoites of T. gondii RH-strain, based on: the free and nieosomal compounds of curcumin and silymarin, in addition to the drug clindamycin. Data were collected to estimate parasite viability during exposure to the therapeutic compounds under study using a special MTT assay ((3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolioum bromide) assay: is a colorimetric assay for measuring cellular growth) kit provided by (Bio Idea Company, Tehran, Iran). Hence, the effect of the therapeutic compounds on the parasite load was studied using the quantitative molecular technique real-time PCR. Results: The results indicate that the combination of N-silymarin and N-curcumin with clindamycin has active synergistic effects against T. gondii leading to complete elimination of the parasite. Data revealed that curcumin and silymarin in both their free and nisomal forms had inhibitory effects on the parasite, and minimal toxic effects on normal cells. Conclusions: The results highlight the successful synergistic effect of clindamycin and the niosomal compounds curcumin and silymarin in completely eradicating the T. gondii RH-strain. This finding contributes positively to the field of safe and effective treatments.