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On the basis of a streamlined route to the pyrroloiminoquinone (PIQ) core, we made 16 natural products spread across four classes of biosynthetically related alkaloid natural products, and multiple structural analogs, all in ≤8 steps longest linear sequence (LLS). The strategy features a Larock indole synthesis as the key operation in a five-step synthesis of a key methoxy-PIQ intermediate. Critically, this compound was readily diverged via selective methylation of either (or both) of the imine-like or pyrrole nitrogens, which then permitted further divergence by either O-demethylation to o-quinone natural products or displacement of the methoxy group with a range of amine nucleophiles. Based on a single, early report of their potential utility against the malaria parasite, we assayed these compounds against several strains of Plasmodium falciparum, as well as two species of the related protozoan parasite Babesia. In combination with evaluations of their human cytotoxicity, we identified several compounds with potent (low-nM IC50) antimalarial and antibabesial activities that are much less toxic toward mammalian cells and are therefore promising lead compounds for antiprotozoal drug discovery.

UNLABELLED: In an effort to identify novel compounds with potent inhibition against Toxoplasma gondii, a phenotypic screen was performed utilizing a library of 683 pure compounds derived primarily from terrestrial and marine fungi. An initial screen with a fixed concentration of 5 µM yielded 91 hits with inhibition comparable to an equal concentration of artemisinin. These compounds were then triaged based on known biological and chemical concerns and liabilities. From these, 49 prioritized compounds were tested in a dose response format with T. gondii and human foreskin fibroblasts (HFFs) for cytotoxicity. Ten compounds were identified with an IC50 less than 150 nM and a selectivity index (SI) greater than 100. An additional eight compounds demonstrated submicromolar IC50 and SI values equal to or greater than 35. While the majority of these scaffolds have been previously implicated against apicomplexan parasites, their activities in T. gondii were largely unknown. Herein, we report the T. gondii activity of these compounds with chemotypes including xanthoquinodins, peptaibols, heptelidic acid analogs, and fumagillin analogs, with multiple compounds demonstrating exceptional potency in T. gondii and limited toxicity to HFFs at the highest concentrations tested. IMPORTANCE: Current therapeutics for treating toxoplasmosis remain insufficient, demonstrating high cytotoxicity, poor bioavailability, limited efficacy, and drug resistance. Additional research is needed to develop novel compounds with high efficacy and low cytotoxicity. The success of artemisinin and other natural products in treating malaria highlights the potential of natural products as anti-protozoan therapeutics. However, the exploration of natural products in T. gondii drug discovery has been less comprehensive, leaving untapped potential. By leveraging the resources available for the malaria drug discovery campaign, we conducted a phenotypic screen utilizing a set of natural products previously screened against Plasmodium falciparum. Our study revealed 18 compounds with high potency and low cytotoxicity in T. gondii, including four novel scaffolds with no previously reported activity in T. gondii. These new scaffolds may serve as starting points for the development of toxoplasmosis therapeutics but could also serve as tool compounds for target identification studies using chemogenomic approach.

Amidine-containing compounds are primarily known as antiprotozoal agents (pentamidine, diminazene, furamidine) or as serine protease inhibitors (nafamostat, sepimostat, camostat, gabexate). DAPI is widely recognized as a fluorescent DNA stain. Recently, it has been shown that these compounds also act as NMDA receptor inhibitors. In this study, we examined the activity of these compounds and analyzed the mechanisms of action in relation to another important class of ionotropic glutamate receptors-calcium-permeable AMPA receptors (CP-AMPARs) and calcium-impermeable AMPA receptors (CIAMPARs) - using the whole-cell patch-clamp method on isolated male Wistar rat brain neurons. Gabexate and camostat were found to be inactive. Other compounds preferentially inhibited calcium-permeable AMPA receptors with IC50 values of 30-60 µM. DAPI and furamidine were also active against CIAMPARs with IC50s of 50-60 µM, while others showed poor activity. All active compounds acted as channel blockers, which are able for permeating into the cytoplasm on both CP- and CI-AMPARs. Specifically, sepimostat showed trapping in the closed CP-AMPAR channel. Furamidine and DAPI demonstrated a voltage-independent action on CI-AMPARs, indicating binding to an additional superficial site. While the majority of compounds inhibited glutamate-activated steady-state currents as well as kainate-activated currents on CI-AMPARs, pentamidine significantly potentiated glutamate-induced steadystate responses. The potentiating effect of pentamidine resembles the action of the positive allosteric modulator cyclothiazide although the exact binding site remains unclear. Thus, this study, together with our previous research on NMDA receptors, provides a comprehensive overview of this novel group of ionotropic glutamate receptors inhibitors with a complex pharmacological profile, remarkable diversity of effects and mechanisms of action. [ABSTRACT FROM AUTHOR]

Background/Objectives: In this study, the efficacy of benzo[h]chromene derivatives as antiprotozoal and antimycobacterial agents was explored. Methods: A total of twenty compounds, including benzo[h]chromene alkyl diesters and benzo[h]chromene-triazole derivatives, were synthesized and tested against Trypanosoma cruzi, Leishmania braziliensis, L. infantum, and strains of Mycobacterium abscessus and Mycobacterium intracellulare LIID-01. Notably, compounds 1a, 1b, 2a, and 3f exhibited superior activity against Trypanosoma cruzi, with IC50 values of 19.2, 37.3, 68.7, and 24.7 µM, respectively, outperforming the reference drug benznidazole (IC50: 54.7 µM). Results: Compounds 1b and 3f showed excellent selectivity indices against Leishmania braziliensis, with SI values of 19 and 18, respectively, suggesting they could be potential alternatives to the commonly used, but more selective, miltefosine (IC50: 64.0 µM, SI: 43.0). Additionally, compounds 1a, 1b, and 3f were most effective against Leishmania infantum, with IC50 values of 24.9, 30.5, and 46.6 µM, respectively. Compounds 3f and 3h were particularly potent against various Mycobacterium abscessus strains, highlighting their significance given the inherent resistance of these bacteria to standard antimicrobials. Conclusions: The sensitivity of Mycobacterium intracellulare LIID-01 to these compounds also underscored their potential in managing infections by the Mycobacterium avium–intracellulare complex. [ABSTRACT FROM AUTHOR]

Naphthylimides play a pivotal role as aromatic heterocyclic compounds, serving as the foundational structures for numerous pharmacologically significant drugs. These drugs encompass antibacterial, antifungal, anticancer, antimalarial, antiviral, anti-inflammatory, antithrombotic, and antiprotozoal agents. The planar and heteroaromatic characteristics of naphthylimides grant them a strong ability to intercalate into DNA. This intercalation property renders naphthylimide derivatives highly valuable for various biological activities. The advantageous pharmacological activity and ease of synthesis associated with naphthylimides and their derivatives provide significant benefits in the design and development of new compounds within this class. Currently, only a few such molecules are undergoing preclinical and clinical evaluations. In this paper, we have compiled the literature on naphthylimides reported by researchers from 2006 to 2024. Our focus lies on exploring the pharmacological activities of their analogues from a drug development and discovery perspective, while examining their structure–activity relationship and mechanisms of action. [ABSTRACT FROM AUTHOR]

Nitroimidazoles are well-known antibacterial and antiprotozoal agents, effective against various infections. However, they may also exhibit genotoxic, carcinogenic and mutagenic effects. This study aimed to develop an analytical method to quantify nitroimidazole residues and their metabolites in honey using Ultra Performance Liquid Chromatography coupled with Orbitrap High-Resolution Mass Spectrometry (UPLC-Orbitrap-HRMS) and validate it according to Commission Implementing Regulation (EU) 2021/808. The method demonstrated limits of detection (LODs) ranging from 0.01 to 0.17 µg L−1 and limits of quantification (LOQs) from 0.020 to 0.29 µg L−1. Recovery rates ranged from 79.8% to 104%, with relative standard deviations (RSDs) between 4.2% and 19.6%. Analysis of 96 honey samples revealed nitroimidazole residues in 18.8% of them. These findings could enhance more effectively the Egyptian monitoring programs for these compounds in honey as to improve food safety. [ABSTRACT FROM AUTHOR]

Trypanosoma cruzi is a protozoan parasite that causes Chagas disease in humans. The current antichagasic drugs nifurtimox and benznidazole have inconveniences of toxicity; therefore, the search for alternative therapeutic strategies is necessary. The present study reports the synthesis, drug-likeness predictions, and in vitro anti-trypanosome activity of a series of 14 quinazoline 2,4,6-triamine derivatives. All compounds were tested against T. cruzi (epimastigotes and trypomastigotes) and in HFF1 human foreskin fibroblasts. The bioassays showed that compounds 2–4 containing nitrobenzoyl substituents at 6-position of the quinazoline 2,4,6-triamine nucleus were the most potent on its antiprotozoal activity. The effect was observed at 24 h and it was preserved for at least 5 days. Also, compounds 2–4 were not toxic to the human control cells, showing high selectivity index. The quinazoline nitro derivatives have potential use as antichagasic agents. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the anti-inflammatory and antiprotozoal effects as well as chemical profile of ethanol extracts of Hedyotis diffusa (Rubiaceae) (HDE) and Scutellaria barbata (Lamiaceae) (SBE). Methods: Dried whole plants collected in Vietnam were extracted with ethanol (30 and 96 %) by maceration for 4 weeks. The resulting extracts obtained after evaporating the solvent were stored in a refrigerator at 4 oC. Mouse carrageenan-induced inflammation and mouse macrophage cell line RAW264.7 were used to assess the in vivo and in vitro anti-inflammatory activities, respectively, while ciliate, Tetrahymena pyriformis was used to determine antiprotozoal effects. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was employed to analyze the chemical profiles of the extracts. Results: All the extracts manifested anti-inflammatory effects in vitro and in vivo. The HDE exhibited significantly higher in vitro anti-inflammatory activity than SBE (p < 0.05). Furthermore, in vivo antiinflammatory activity was higher in SBE compared to HDE. Both extracts exhibited antiprotozoal effects. The 96 % ethanol extract of both plants were more active than the 30 % ethanol extracts. Analysis by UHPLC-Q-TOF-MS revealed the presence of chrysin, apigenin and apigenin derivatives, naringenin, wogonin, quercetin and quercetin derivatives, as well as scutellarin. Conclusion: The HDE and SBE extracts from Vietnam exhibit significant in vivo and in vitro antiinflammatory activities and in addition, antiprotozoal activity against Tetrahymena pyriformis. These plants, therefore, are potential sources of antiprotozoal agents. [ABSTRACT FROM AUTHOR]

The aim of this work was to obtain and evaluate, as antiprotozoals, new derivatives of benzoate imidazo-1,3,4-thiadiazole 18–23 based on the concepts of molecular repositioning and hybridization. In the design of these compounds, two important pharmacophoric subunits of the fexnidazole prototype were used: metronidazole was used as a repositioning molecule, p-aminobenzoic acid was incorporated as a bridge group, and 1,3,4-thiadiazole group was incorporated as a second pharmacophore, which at position 5 has an aromatic group with different substituents incorporated. The final six compounds were obtained through a five-step linear route with moderate to good yields. The biological results demonstrated the potential of this new class of compounds, since three of them 19–21 showed inhibitory activity on proliferation, in the order of 50%, in the in vitro assay against epimastigotes of T. cruzi (Strain Y sensitive to nifurtimox and benznidazole) and promastigotes of L. donovani, at a single concentration of 50 μM. [ABSTRACT FROM AUTHOR]

Background/Objectives: While multiple studies have investigated antibiotic consumption rates, there are few studies on the consumption of systemic antifungals and antiprotozoals. This study aims to fill this gap by providing a comprehensive analysis of nationwide consumption trends in Kazakhstan over a seven-year period (2017–2023). Methods: Defined daily doses per 1000 inhabitants per day were calculated for systemic antifungals (J02 code of the Anatomical Therapeutic Chemical Classification System (ATC)) and antiprotozoals (P01 code of the ATC). Time series analyses were applied to examine historical trends, evaluate the impact of the COVID-19 pandemic, and make future projections until 2030. Results: The total consumption increased over the study period, with an average annual percent change of 1.11% for antifungals and 5.48% for antiprotozoals. Fluconazole was the most consumed antifungal agent, whereas metronidazole was the most consumed antiprotozoal agent. The COVID-19 pandemic had a positive but insignificant effect on the consumption of antifungals and a negative and also insignificant effect on the consumption of antiprotozoals. Forecast modeling indicates that the future trends in antifungal and antiprotozoal consumption until 2030 will largely remain stable, with the exception of antiprotozoal consumption in the hospital sector, which is projected to decline. Conclusions: These findings offer valuable insights into the development and implementation of targeted antimicrobial stewardship programs in Kazakhstan. [ABSTRACT FROM AUTHOR]

Leishmaniases are a collection of neglected tropical diseases caused by kinetoplastid parasites in the genus Leishmania. Current chemotherapies are severely limited, and the need for new antileishmanials is of pressing international importance. Bromodomains are epigenetic reader domains that have shown promising therapeutic potential for cancer therapy and may also present an attractive target to treat parasitic diseases. Here, we investigate Leishmania donovani bromodomain factor 5 (LdBDF5) as a target for antileishmanial drug discovery. LdBDF5 contains a pair of bromodomains (BD5.1 and BD5.2) in an N-terminal tandem repeat. We purified recombinant bromodomains of L. donovani BDF5 and determined the structure of BD5.2 by X-ray crystallography. Using a histone peptide microarray and fluorescence polarization assay, we identified binding interactions of LdBDF5 bromodomains with acetylated peptides derived from histones H2B and H4. In orthogonal biophysical assays including thermal shift assays, fluorescence polarization, and NMR, we showed that BDF5 bromodomains bind to human bromodomain inhibitors SGC-CBP30, bromosporine, and I-BRD9; moreover, SGC-CBP30 exhibited activity against Leishmania promastigotes in cell viability assays. These findings exemplify the potential BDF5 holds as a possible drug target in Leishmania and provide a foundation for the future development of optimized antileishmanial compounds targeting this epigenetic reader protein.

The first successful heart transplant was carried out in 1979, and there are now approximately 200 transplants undertaken in the UK each year. Many medications are used to prevent rejection of the transplanted organ, but this needs to be balanced with the risk of complications of immunosuppression, such as infection, organ dysfunction, graft dysfunction and vasculopathy. Patients must be able to adhere to the complex and vast regimen of medications started post-transplant, and extensive monitoring is required to ensure the correct balance of rejection risk and adverse effects, depending on where the patient is in their postoperative journey. Immediately after the transplant is when the patient is at highest risk of rejecting their new heart. Guidance is available to recommend regimens to prevent rejection, but needs to be adapted to each patient, taking into consideration their clinical picture, together with comorbidities, drug interactions and organ dysfunction. [ABSTRACT FROM AUTHOR]

A multistep sequence leads to the preparation of a series of aryl selenocyanate WC‐9 homologues, which are interesting compounds with potential biological activity against Trypanosoma cruzi, the etiological agent of Chagas disease. The synthetic sequence involves the application of the photo‐Fries rearrangement reaction as a key step for the preparation of a series of 2‐hydroxyphenones bearing alkyl chains of different length and a phenyl group. These intermediates are obtained upon direct irradiation (254 nm) of 4‐phenoxyphenyl esters in different solvents at room temperature. Then, reaction of the 2‐hydroxyphenones with 2‐(2‐bromoethoxy)tetrahydro‐2H‐pyran followed by acid deprotection, tosylation (or mesylation) reaction and, finally, nucleophilic attack with potassium selenocyanate provides the target aryloxyethyl selenocyanate homologues in good yields. [ABSTRACT FROM AUTHOR]

Babesiosis is a disease caused by intraerythrocytic protozoal parasites, which occurs in animals and humans. In dogs, babesiosis can be caused by eight species of Babesia gene: i.e., B. canis, B. rossi, B. vogeli, B. coco, B. gibsoni, B. conradae, B., and B. negevi, which are bound to certain geographical areas. The disease has a focal nature and its transmission depends mainly on vectors, which are ticks of various species. Due to transstadial, and transovarial transmission, babesiosis is able to persist in natural foci in several generations of ticks, even without the presence of a susceptible host. Typical clinical signs associated with canine babesiosis are: fever, apathy, weakness, pale mucous membranes, icterus and hemoglobinuria. The disease can have an acute or peracute course, and subclinical and subacute infections have also been described. The clinical manifestations of babesiosis may vary depending on the particular species and strains, and their specific virulence, but also depending on factors that determine the host's response to infection, such as age, individual immune status, and the presence of concurrent infections or other diseases. Medicines, from the group of antiprotozoans, a selected group of antibiotics, or their combinations are used for therapy. There are differences in the therapy of babesiosis depending on the Babesia species, the animal is often cured of the acute phase, but the parasite remains in the organism. [ABSTRACT FROM AUTHOR]

The structures of the pentavalent antimonials, small-molecule Sb-containing drugs used to treat the neglected tropical disease leishmaniasis, remain unknown despite their widespread use for over half a century. These drugs are prepared by combination of an Sb(V) precursor and a sugar derivative and proposed structures frequently invoke a cyclic stiborane motif in which a vicinal diolate ligand chelates an Sb(V) center. As a step towards better understanding the structures of the pentavalent antimonial drugs, a series of cyclic organostiboranes spanning the stereochemical space afforded by a vicinal diolate motif has been synthesized and characterized. X-ray crystallography and NMR spectroscopy provide unambiguous characterization of the structures of these model compounds and of the interaction of the diolate with the Sb(V) center. Particularly notable are the systematic trends observed in the NMR spectroscopic signals as a function of the stereochemistry of the diolate. The spectroscopic signatures identified with these model compounds will provide a framework for elucidating the structures of the pentavalent antimonial drugs.

Nitrogenous heterocyclic rings are present in a wide range of drugs, natural compounds, and fine chemicals and are considered privileged scaffolds in medicinal chemistry. Seeking novel anti‐protozoal drugs acting on new targets or by novel mechanisms of action, we focused on a preliminary evaluation of the potential of "linear‐shaped" diaryl pyrazines. To this purpose, a two‐enzyme chemoenzymatic synthesis of this heteroaromatic core was carried out. Specifically, starting from simple, commercially available aromatic aldehydes, the target pyrazines were obtained through a sequence of biocatalytic benzoin condensation, chemical oxidation and a transaminase‐mediated tandem process of transamination and cyclization. The profiles of the compounds as antiprotozoal agents were evaluated in vitro against parasites cultures of the Leishmania and Plasmodium genera and using the human cell line HepG2. [ABSTRACT FROM AUTHOR]

Trypanosoma cruzi is a protozoan parasite that causes Chagas disease in humans. The current antichagasic drugs nifurtimox and benznidazole have inconveniences of toxicity; therefore, the search for alternative therapeutic strategies is necessary. The present study reports the synthesis, drug-likeness predictions, and in vitro anti-trypanosome activity of a series of 14 quinazoline 2,4,6-triamine derivatives. All compounds were tested against T. cruzi (epimastigotes and trypomastigotes) and in HFF1 human foreskin fibroblasts. The bioassays showed that compounds 2–4 containing nitrobenzoyl substituents at 6-position of the quinazoline 2,4,6-triamine nucleus were the most potent on its antiprotozoal activity. The effect was observed at 24 h and it was preserved for at least 5 days. Also, compounds 2–4 were not toxic to the human control cells, showing high selectivity index. The quinazoline nitro derivatives have potential use as antichagasic agents.

Background/Objectives: While multiple studies have investigated antibiotic consumption rates, there are few studies on the consumption of systemic antifungals and antiprotozoals. This study aims to fill this gap by providing a comprehensive analysis of nationwide consumption trends in Kazakhstan over a seven-year period (2017–2023). Methods: Defined daily doses per 1000 inhabitants per day were calculated for systemic antifungals (J02 code of the Anatomical Therapeutic Chemical Classification System (ATC)) and antiprotozoals (P01 code of the ATC). Time series analyses were applied to examine historical trends, evaluate the impact of the COVID-19 pandemic, and make future projections until 2030. Results: The total consumption increased over the study period, with an average annual percent change of 1.11% for antifungals and 5.48% for antiprotozoals. Fluconazole was the most consumed antifungal agent, whereas metronidazole was the most consumed antiprotozoal agent. The COVID-19 pandemic had a positive but insignificant effect on the consumption of antifungals and a negative and also insignificant effect on the consumption of antiprotozoals. Forecast modeling indicates that the future trends in antifungal and antiprotozoal consumption until 2030 will largely remain stable, with the exception of antiprotozoal consumption in the hospital sector, which is projected to decline. Conclusions: These findings offer valuable insights into the development and implementation of targeted antimicrobial stewardship programs in Kazakhstan.

Despite tremendous advances in the prevention and treatment of infectious diseases, only few antiparasitic drugs have been developed to date. Protozoan infections such as malaria, leishmaniasis, and trypanosomiasis continue to exact an enormous toll on public health worldwide, underscoring the need to discover novel antiprotozoan drugs. Recently, there has been an explosion of research into the antiprotozoan properties of quercetin, one of the most abundant flavonoids in the human diet. In this review, we tried to consolidate the current knowledge on the antiprotozoal effects of quercetin and to provide the most fruitful avenues for future research. Quercetin exerts potent antiprotozoan activity against a broad spectrum of pathogens such as Leishmania spp., Trypanosoma spp., Plasmodium spp., Cryptosporidium spp., Trichomonas spp., and Toxoplasma gondii. In addition to its immunomodulatory roles, quercetin disrupts mitochondrial function, induces apoptotic/necrotic cell death, impairs iron uptake, inhibits multiple enzymes involved in fatty acid synthesis and the glycolytic pathways, suppresses the activity of DNA topoisomerases, and downregulates the expression of various heat shock proteins in these pathogens. In vivo studies also show that quercetin is effective in reducing parasitic loads, histopathological damage, and mortality in animals. Future research should focus on designing effective drug delivery systems to increase the oral bioavailability of quercetin. Incorporating quercetin into various nanocarrier systems would be a promising approach to manage localized cutaneous infections. Nevertheless, clinical trials are needed to validate the efficacy of quercetin in treating various protozoan infections. [ABSTRACT FROM AUTHOR]

Protozoal diseases, including leishmaniasis, malaria, African sleeping sickness, Chagas disease, amoebiasis, giardiasis, cryptococcosis, and toxoplasmosis, are significant global health concerns affecting over one billion people. This special issue of Pharmaceuticals presents research on alternative drug designs and discoveries for antiprotozoal agents. The articles discuss the potential use of various drugs and compounds for the treatment of protozoal diseases, including terfenadine, nitazoxanide, herbal medicine, essential oils, nanoparticles, riluzole, and derivatives. The studies employ different approaches such as drug repurposing, natural product exploration, and conventional drug design strategies. The research also utilizes molecular docking and simulations to evaluate the effectiveness of compounds against these parasites. Overall, the articles provide promising findings that contribute to ongoing research in the field of protozoan disease drug development. [Extracted from the article]

Caffeic acid (CA) is one of the most abundant natural compounds present in plants and has a broad spectrum of beneficial pharmacological activities. However, in some cases, synthetic derivation of original molecules can expand their scope. This study focuses on the synthesis of caffeic acid phosphanium derivatives with the ambition of increasing their biological activities. Four caffeic acid phosphanium salts (CAPs) were synthesized and tested for their cytotoxic, antibacterial, antifungal, and amoebicidal activity in vitro, with the aim of identifying the best area for their medicinal use. CAPs exhibited significantly stronger cytotoxic activity against tested cell lines (HeLa, HCT116, MDA-MB-231 MCF-7, A2058, PANC-1, Jurkat) in comparison to caffeic acid. Focusing on Jurkat cells (human leukemic T cell lymphoma), the IC50 value of CAPs ranged from 0.9 to 8.5 μM while IC50 of CA was >300 μM. Antimicrobial testing also confirmed significantly higher activity of CAPs against selected microbes in comparison to CA, especially for Gram-positive bacteria (MIC 13–57 μM) and the yeast Candida albicans (MIC 13–57 μM). The anti-Acanthamoeba activity was studied against two pathogenic Acanthamoeba strains. In the case of A. lugdunensis, all CAPs revealed a stronger inhibitory effect (EC50 74–3125 μM) than CA (>105 µM), while in A. quina strain, the higher inhibition was observed for three derivatives (EC50 44–291 μM). The newly synthesized quaternary phosphanium salts of caffeic acid exhibited selective antitumor action and appeared to be promising antimicrobial agents for topical application, as well as potential molecules for further research. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations have been developed as the most powerful tool in the field of computational chemistry for the discovery of novel anti‐protozoal agents against malaria. In this review, the recent advancements and developments in the field of molecular dynamics simulations driven identification and optimization of promising anti‐protozoal agents have been highlighted along with the use of advanced simulation softwares, energy calculations, stability parameters, and many more. To the best of our knowledge, the present work has been the first review article to highlight the use of molecular dynamics simulations for the discovery of anti‐plasmodial agents with the aim to dig out the significant insights into the simulations having the applications for the benefit of computational and medicinal chemists. [ABSTRACT FROM AUTHOR]

Background: Trichomoniasis is one of the most common sexually transmitted infections worldwide. The growing concern of drug resistance of this infection has cautioned the need for new drug development. We evaluated the potential antiproliferative and apoptotic effect of a-pinene and tannic acid (TA) on Trichomonas vaginalis cells. In addition, the cytotoxicity of agents on Vero cells was investigated. Methods: Trichomonas cells were axenically cultured in TYI-S-33 medium. In vitro antiproliferative activity of a-pinene, TA, and metronidazole was investigated against Trichomonas cells. The assays were carried out in triplicate using microtiter plate and trypan blue staining method. Annexin V/PI staining with flow cytometry was used to evaluate apoptosis induction. In addition, the cytotoxic effect was measured by MTT assay. Results: α-Pinene and TA exhibited significant inhibition of the Trichomonas cells and the lowest IC50 values were 22.9 µg/ml and 140 µg/ml at 48 hours' incubation, respectively. The CC50 was found at 116 μg/ml for β-pinene and 473 μg/ml for TA, after 48 hours of treatment. The flow cytometry study demonstrated that the natural compounds induced apoptosis in Trichomonas cells. After 24 hours of treatment, the induction of apoptosis was 5.2% - 36.6% at concentrations of 3.9 - 62.5 μg/ml for β-pinene and TA induced-apoptosis was 6.1% - 53.8% at concentrations of 125-2000 μg/ml. Conclusion: Although the results show the antiproliferative and apoptotic effect of a-pinene and TA on Trichomonas cells, in vivo studies are needed to further clarify the effects of these compounds. [ABSTRACT FROM AUTHOR]

Background: Leishmaniasis is a parasitic disease caused by the Leishmania parasite, transmitted to humans through the bite of an infected sand-fly. The disease manifests in four primary clinical manifestations: visceral, cutaneous, diffuse cutaneous, and post-kalaazar dermal. The disease's clinical manifestations depend on the Leishmania species and their immune response. Current antileishmanial drugs include amphotericin B, antimonials, sitamaquine, pentamidine, paromomycin, and miltefosine. However, these drugs have drawbacks, such as resistance to pentavalent antimonials and nephrotoxicity. The World Health Organization suggests using plants as a healing agent with good efficacy and affordability. Conyza Canadensis, a biennial plant, has been used for wound healing and has shown efficacy against gram-positive and gram-negative bacteria. Objective: The study aimed to investigate the anti-leishmanial activity of extracts from Conyza Canadensis, on Iraqi strain of Leishmania tropica. Material and method: The phytochemical compounds were found in the extraction process, with total alkaloid content, phenolic compounds, flavonoid content, amino acid analysis, and total glycosides. The extract was prepared into stock solutions and sub-cultured in RPMI-1640. The cells were then incubated in tissue culture flasks and treated with different concentrations of SSG and aqueous/alcoholic extracts. The anti-leishmanial activity of the extracts was then evaluated using the sandwich enzyme-linked immunosorbent assay (ELISA) technique. The results showed that the extracts had anti-leishmanial activity. Result: the study shows that Iraqi C. canadensis plant extract contains alkaloids, gallic acid, apigenin, chlorogenic acid, caffeineic acid, quercetin, p-cumaric acid, and GSH, which reduce neopterin levels and activate immune response against L. tropica. Conclusion: Conyza Canadensis extracts show anti-leishmanial activity, correlated with neopterin levels, promising as an alternative therapy for leishmaniasis. Further research is needed for effectiveness. [ABSTRACT FROM AUTHOR]

Toxoplasmosis is a common protozoan infection that can have severe outcomes in the immunocompromised and during pregnancy, but treatment options are limited. Recently, nucleotide metabolism has received much attention as a target for new antiprotozoal agents and here we focus on pyrimidine salvage by Toxoplasma gondii as a drug target. Whereas uptake of [³H]-cytidine and particularly [³H]-thymidine was at most marginal, [³H]-uracil and [³H]-uridine were readily taken up. Kinetic analysis of uridine uptake was consistent with a single transporter with a Km of 3.3 ± 0.8 µM, which was inhibited by uracil with high affinity (Ki = 1.15 ± 0.07 µM) but not by thymidine or 5-methyluridine, showing that the 5-Me group is incompatible with uptake by T. gondii. Conversely, [³H]-uracil transport displayed a Km of 2.05 ± 0.40 µM, not significantly different from the uracil Ki on uridine transport, and was inhibited by uridine with a Ki of 2.44 ± 0.59 µM, also not significantly different from the experimental uridine Km. The reciprocal, complete inhibition, displaying Hill slopes of approximately -1, strongly suggest that uridine and uracil share a single transporter with similarly high affinity for both, and we designate it uridine/uracil transporter 1 (TgUUT1). While TgUUT1 excludes 5-methyl substitutions, the smaller 5F substitution was tolerated, as 5F-uracil inhibited uptake of [³H]-uracil with a Ki of 6.80 ± 2.12 µM (P > 0.05 compared to uracil Km). Indeed, we found that 5F-Uridine, 5F-uracil and 5F,2’-deoxyuridine were all potent antimetabolites against T. gondii with EC50 values well below that of the current first line treatment, sulfadiazine. In vivo evaluation also showed that 5F-uracil and 5F,2’-deoxyuridine were similarly effective as sulfadiazine against acute toxoplasmosis. Our preliminary conclusion is that TgUUT1 mediates potential new anti-toxoplasmosis drugs with activity superior to the current treatment. [ABSTRACT FROM AUTHOR]

Background: In the last few decades, the use of plant extracts and their phytochemicals as candidates for the management of parasitic diseases has increased tremendously. Irises are aromatic and medicinal plants that have long been employed in the treatment of different infectious diseases by traditional healers in many cultures. This study aims to explore the potential of three common Iris species (I. confusa Sealy, I. pseudacorus L. and I. germanica L.) against infectious diseases. Their in vitro antiprotozoal potency against Plasmodium falciparum, Trypanosoma brucei brucei, T. b. rhodesiense, T. cruzi and Leishmania infantum beside their cytotoxicity on MRC-5 fibroblasts and primary peritoneal murine macrophages were examined. Methods: The secondary metabolites of the tested extracts were characterized by UPLC-HRMS/MS and Pearsons correlation was used to correlate them with the antiprotozoal activity. Results: Overall, the non-polar fractions (NPF) showed a significant antiprotozoal activity (score: sc 2 to 5) in contrast to the polar fractions (PF). I. confusa NPF was the most active extract against P. falciparum [IC50 of 1.08 μg/mL, selectivity index (S.I. 26.11) and sc 5] and L. infantum (IC50 of 12.7 μg/mL, S.I. 2.22 and sc 2). I. pseudacorus NPF was the most potent fraction against T. b. rhodesiense (IC50 of 8.17 μg/mL, S.I. 3.67 and sc 3). Monogalactosyldiacylglycerol glycolipid (18:3/18:3), triaceylglycerol (18:2/18:2/18:3), oleic acid, and triterpenoid irridals (spirioiridoconfal C and iso-iridobelamal A) were the top positively correlated metabolites with antiplasmodium and antileishmanial activities of I. confusa NPF. Tumulosic acid, ceramide sphingolipids, corosolic, maslinic, moreollic acids, pheophytin a, triaceylglycerols, mono- and digalactosyldiacylglycerols, phosphatidylglycerol (22:6/18:3), phosphatidylcholines (18:1/18:2), and triterpenoid irridal iso-iridobelamal A, were highly correlated to I. pseudacorus NPF anti- T. b. rhodesiense activity. The ADME study revealed proper drug likeness properties for certain highly corelated secondary metabolites. Conclusion: This study is the sole map correlating I. confusa and I. pseudacorus secondary metabolites to their newly explored antiprotozoal activity. [ABSTRACT FROM AUTHOR]

This document is a summary of a special issue that focuses on the exploration of natural products with antiprotozoal activity. The articles in the special issue discuss the efficacy of various natural compounds against protozoan parasites, such as Trypanosoma brucei and Plasmodium falciparum. The studies highlight the potential of these natural products as alternative treatments for tropical diseases and emphasize the need for further research and development in this field. Additionally, the special issue includes a review of next-generation human liver models for antimalarial drug assays, which discusses the challenges and potential of using stem cells and organoids for drug discovery. The document concludes by mentioning the potential of combining natural-based antiprotozoal agents with existing drugs, elucidating the mechanisms of action of natural compounds, and developing plant-based vaccines for protozoal diseases. [Extracted from the article]

Context: Cutaneous leishmaniasis is a disease of public health importance; treatment is based on the use of pentavalent antimonials with high toxicity and low efficacy; therefore, it´s necessary to search for therapeutic alternatives derived from natural products, based on the study of medicinal plants as a source of molecules with highly effective leishmanicidal potential. Aims: To carry out a systematic review between 2018 and 2022 on medicinal plants with potential leishmanicidal activity on parasite strains from the New World causing cutaneous leishmaniasis. Methods: The review study was conducted in four phases following the PRISMA methodology. First, research questions and objectives were formulated to establish the topic areas and construct the search algorithm. Second, a search was performed across different databases, including ScienceDirect, Scopus, PubMed, Web of Science, EBSCO, Taylor and Francis, and Scielo. Third, articles were chosen based on specific inclusion and exclusion criteria. Finally, the relevant information for the review was systematically organized. Results: The search yielded 163 articles, and 12 of them were selected as the basis for the construction of the review. Ethanolic and aqueous extracts stand out, as well as biocompounds such as terpenes and flavonoids. Antioxidant activity on reactive oxygen species was the most frequently cited. Conclusions: Promising terpene and flavonoid molecules with high antileishmanial activity (IC50 1) were identified in this study; these findings provide a scientific basis for the traditional use that communities have given to plants as a therapeutic source to treat cutaneous leishmaniasis in the New World.

Introduction: Naegleria fowleri is responsible for primary amebic meningoencephalitis (PAM) which has a fatality rate of >97%. Because of the rarity of the disease, pharmaceutical companies do not pursue new drug discovery for PAM. Yet, it is possible that the infection is underreported and finding a better drug would have an impact on people suffering from this deadly infection.Areas covered: This paper reports the efforts undertaken by different academic groups over the last 20 years to test different compounds against N. fowleri. The drug discovery research encompassed synthesis of new compounds, development and use of high-throughput screening methods and attempts to repurpose clinically developed or FDA-approved compounds for the treatment of PAM.Expert opinion: In absence of economic investment to develop new drugs for PAM, repurposing the FDA-approved drugs has been the best strategy so far to identify new leads against N. fowleri. Increasing use of high-throughput phenotypic screening has the potential to accelerate the identification of new leads, either in monotherapy or in combination treatment. Since phase II clinical trial is not possible for PAM, it is critical to demonstrate in vivo efficacy of a clinically safe compound to translate the discovery from lab to the clinic.

Background: Trichomoniasis is one of the most common sexually transmitted infections worldwide. The growing concern of drug resistance of this infection has cautioned the need for new drug development. We evaluated the potential antiproliferative and apoptotic effect of α-pinene and tannic acid (TA) on Trichomonas vaginalis cells. In addition, the cytotoxicity of agents on Vero cells was investigated. Methods: Trichomonas cells were axenically cultured in TYI-S-33 medium. In vitro antiproliferative activity of α-pinene, TA, and metronidazole was investigated against Trichomonas cells. The assays were carried out in triplicate using microtiter plate and trypan blue staining method. Annexin V/PI staining with flow cytometry was used to evaluate apoptosis induction. In addition, the cytotoxic effect was measured by MTT assay. Results: α-Pinene and TA exhibited significant inhibition of the Trichomonas cells and the lowest IC50 values were 22.9 µg/ml and 140 µg/ml at 48 hours’ incubation, respectively. The CC50 was found at 116 μg/ml for α-pinene and 473 μg/ml for TA, after 48 hours of treatment. The flow cytometry study demonstrated that the natural compounds induced apoptosis in Trichomonas cells. After 24 hours of treatment, the induction of apoptosis was 5.2% - 36.6% at concentrations of 3.9 - 62.5 μg/ml for α-pinene and TA induced-apoptosis was 6.1% - 53.8% at concentrations of 125-2000 μg/ml. Conclusion: Although the results show the antiproliferative and apoptotic effect of α-pinene and TA on Trichomonas cells, in vivo studies are needed to further clarify the effects of these compounds.

Chagas disease (CD) is one of extremely Neglected Tropical Diseases (NTD) that have been challenging the health of billions of people in the world. Despite being a threat worldwide many of these diseases have a scarce chemotherapeutic armamentarium and the drugs currently used are not effective because of several reason, such as drug resistance, serious side‐effects, among others. Only two drugs are currently available for CD therapeutics, and they are not active in the chronic phase of the diseases. Considering the huge necessity of drugs for this parasitosis, the search for either new or better drugs than those used, many research groups have been involved in this investigation. New scaffolds can be used with this purpose and piperazine is one of them. Since it has many chemical, pharmacological and pharmacokinetics advantages, including multitarget activity, this group has been often used in CD. In this review, which the role of piperazine group in the structure‐activity of some important targets for T. cruzi, as cruzain, trypanothione reductase, Fe‐superoxide dismutase, and nitroreductase as well, is comprehended, several examples have been given to inspire researchers to optimize either hit or lead compounds against T. cruzi. [ABSTRACT FROM AUTHOR]

P450 family, especially CYP51 protein, is a common target for the design of antifungal and antiprotozoal drugs. Designing new effective drugs against these pathogens is a necessity and a challenge for the scientific community. To this end, they are evaluated by molecular docking of five schemes of aryl-substituted imidazoles and pseudopeptic imidazoles against CYP51 proteins from different pathogens and against the similar human protein to estimate their selectivity. Once these calculations have been carried out, none of the compounds studied appears to be an effective inhibitor against CYP51- L.infantum. However, for all the remaining proteins lower normalized coupling scores are obtained, fundamentally for schemes 1 and 3. Given the geometry of the proteinlinked complexes formed, schemes 2 and 4 appear to be more selective than schemes 1, 3 and 5. However, the highest estimated selectivity values are obtained for schemes 1 and 3 against CYP51-C.glabrata and for scheme 1 against CYP51-N.fowleri. In general, the direct relationship between the stability of the protein-ligated complex with the direct interaction of the ligand with the Fe2+ cation of the heme group, which provides stability to the union. [ABSTRACT FROM AUTHOR]

Background: Cutaneous leishmaniasis (CL) is a skin disease caused by protozoan parasites belonging to the Leishmania genus. The most commonly preferred treatment option for CL treatment is pentavalent antimony compounds. The aim of this study is to investigate the clinical characteristics and treatment responses of patients diagnosed with CL treated with systemic antimony. Materials and Methods: This retrospective study included 52 patients diagnosed with CL and treated with systemic antimony in our skin and venereal diseases clinic between May 2018 and May 2020. The clinical and demographic characteristics recorded in the patients' files were examined. Systemic antimony (intramuscular meglumine antimonate (IM MA)) was administered Results: 30 (57.7%) of the patients in our study w ere female a nd 22 (42.3%) were male. The average age of the patients was 26.5±14.23 years. Lesions were most frequently located in the facial region, and noduloulcerative type lesions were most frequently seen. The diagnosis of CL was made by observing amastigotes in the cutaneous smear in 48 (92.3%) patients and in the histopathological examination of the lesioned skin in 4 (7.7%) patients. When the patients receiving IM MA treatment were evaluated at the 12th week in terms of treatment response, complete clinical recovery of the lesions was observed in 50 (96.1%) patients and partial clinical improvement was observed in 2 (3.9%) patients. Conclusions: As a result, the data in our study were similar to the clinical and demographic data on CL previously published in our country. [ABSTRACT FROM AUTHOR]

Trichomonas vaginalis causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against T. vaginalis and other protozoa but has significant human toxicity. In a systematic structure-activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1-C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against T. vaginalis and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live T. vaginalis than the enzyme, suggesting that alternative targets exist. Furthermore, all tested gold(I) complexes acted independently of Mz and were able to overcome Mz resistance, making them candidates for the treatment of Mz-refractory trichomoniasis.

Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure-activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.

This document is an editorial introducing a special issue on drug toxicity. It highlights the toxic effects of various drugs, including ethanol, hydrocodone, heroin, pentylenetetrazol, metronidazole, paracetamol, paclitaxel, and tilmicosin. The editorial also discusses the protective effects of certain agents and plant extracts against drug-induced toxicity. The research articles included in the special issue cover topics such as the attenuation of alcohol dependence, the upregulation of glutamate transporters to mitigate the effects of chronic drug exposure, the use of natural polyphenols to reduce heroin-seeking behaviors, and the teratogenicity and hepatotoxicity risks associated with certain medications during pregnancy. The issue also includes a review article on the poisoning effects of Xylazine in humans. Overall, the special issue provides valuable insights into the pharmacological and toxicological nature of drugs and their potential impacts on the body. [Extracted from the article]

Background Meglumine antimoniate (MA) remains the main treatment for cutaneous leishmaniasis (CL). Uncontrolled studies suggest that intralesional MA (IL-MA) may be noninferior and safer than systemic MA (S-MA). Methods Multicenter, randomized, controlled, open-label, phase 3 clinical trial to evaluate the efficacy and toxicity of IL-MA in 3 infiltrations at 14-day intervals compared with S-MA (10–20 mg Sb5+/kg/day, 20 days) for CL, with noninferiority margin of 20%. Primary and secondary outcomes were definitive cure at day 180 and epithelialization rate at day 90 of treatment, respectively. A 2-year follow-up was performed to assess relapses and emergence of mucosal lesions. Adverse events (AEs) were monitored according to the Division of AIDS AE grading system. Results We evaluated 135 patients. The cure rates (95% confidence interval) for IL-MA and S-MA treatment were, respectively, 82.8% (70.5–91.4) and 67.8% (53.3–78.3) per protocol (PP) and 70.6% (58.3–81.0) and 59.7% (47.0–71.5) per intention to treat (ITT). The epithelialization rates of the IL-MA and S-MA treatment were, respectively, 79.3% (66.6–88 + 8) and 71.2% (57.9–82.2) PP and 69.1% (55.2–78.5) and 64.2% (50.0–74.2) ITT. AEs in the IL-MA and S-MA groups were, respectively, clinical, 45.6% and 80.6%; laboratory, 26.5% and 73.1%; and electrocardiogram, 8.8% and 25.4%. Ten participants in the S-MA group and 1 in the IL-MA group were discontinued due to severe or persistent AEs. Conclusions IL-MA provides a similar cure rate and results in less toxicity compared with S-MA and may be used as first-line therapy for CL patients. Clinical Trials Registration REBEC: RBR-6mk5n4. [ABSTRACT FROM AUTHOR]

The article discusses the use of intralesional antimonial drug treatment for Leishmania braziliensis cutaneous leishmaniasis (CL). It highlights a shift in treatment approach, favoring intralesional pentavalent antimonial drugs (IL SbV) over systemic treatment. It also reviews studies comparing the efficacy and safety of IL SbV with systemic therapy, explores the benefits of IL therapy, and discusses the uncertainties surrounding the risk of developing mucosal leishmaniasis post-treatment.

Most antimicrobial drugs need an intravenous (IV) administration to achieve maximum efficacy against target pathogens. IV administration is related to complications, such as tissue infiltration and thrombo-phlebitis. This systematic review aims to provide practical recommendations about diluent, pH, osmolarity, dosage, infusion rate, vesicant properties, and phlebitis rate of the most commonly used antimicrobial drugs evaluated in randomized controlled studies (RCT) till 31 March 2023. The authors searched for available IV antimicrobial drugs in RCT in PUBMED EMBASE®, EBSCO® CINAHL®, and the Cochrane Controlled Clinical trials. Drugs' chemical features were searched online, in drug data sheets, and in scientific papers, establishing that the drugs with a pH of <5 or >9, osmolarity >600 mOsm/L, high incidence of phlebitis reported in the literature, and vesicant drugs need the adoption of utmost caution during administration. We evaluated 931 papers; 232 studies were included. A total of 82 antimicrobials were identified. Regarding antibiotics, 37 reach the "caution" criterion, as well as seven antivirals, 10 antifungals, and three antiprotozoals. In this subgroup of antimicrobials, the correct vascular access device (VAD) selection is essential to avoid complications due to the administration through a peripheral vein. Knowing the physicochemical characteristics of antimicrobials is crucial to improve the patient's safety significantly, thus avoiding administration errors and local side effects. [ABSTRACT FROM AUTHOR]

Apicomplexan parasites cause severe disease in both humans and their domesticated animals. Since these parasites readily develop drug resistance, development of new, effective drugs to treat infection caused by these parasites is an ongoing challenge for the medical and veterinary communities. We hypothesized that invertebrate-bacterial symbioses might be a rich source of anti-apicomplexan compounds because invertebrates are susceptible to infections with gregarines, parasites that are ancestral to all apicomplexans. We chose to explore the therapeutic potential of shipworm symbiotic bacteria as they are bona fide symbionts, are easily grown in axenic culture and have genomes rich in secondary metabolite loci [1,2]. Two strains of the shipworm symbiotic bacterium, Teredinibacter turnerae, were screened for activity against Toxoplasma gondii and one strain, T7901, exhibited activity against intracellular stages of the parasite. Bioassay-guided fractionation identified tartrolon E (trtE) as the source of the activity. TrtE has an EC50 of 3 nM against T. gondii, acts directly on the parasite itself and kills the parasites after two hours of treatment. TrtE exhibits nanomolar to picomolar level activity against Cryptosporidium, Plasmodium, Babesia, Theileria, and Sarcocystis; parasites representing all branches of the apicomplexan phylogenetic tree. The compound also proved effective against Cryptosporidium parvum infection in neonatal mice, indicating that trtE may be a potential lead compound for preclinical development. Identification of a promising new compound after such limited screening strongly encourages further mining of invertebrate symbionts for new anti-parasitic therapeutics.

Apicomplexan parasites cause severe disease in both humans and their domesticated animals. Since these parasites readily develop drug resistance, development of new, effective drugs to treat infection caused by these parasites is an ongoing challenge for the medical and veterinary communities. We hypothesized that invertebrate-bacterial symbioses might be a rich source of anti-apicomplexan compounds because invertebrates are susceptible to infections with gregarines, parasites that are ancestral to all apicomplexans. We chose to explore the therapeutic potential of shipworm symbiotic bacteria as they are bona fide symbionts, are easily grown in axenic culture and have genomes rich in secondary metabolite loci [1,2]. Two strains of the shipworm symbiotic bacterium, Teredinibacter turnerae, were screened for activity against Toxoplasma gondii and one strain, T7901, exhibited activity against intracellular stages of the parasite. Bioassay-guided fractionation identified tartrolon E (trtE) as the source of the activity. TrtE has an EC50 of 3 nM against T. gondii, acts directly on the parasite itself and kills the parasites after two hours of treatment. TrtE exhibits nanomolar to picomolar level activity against Cryptosporidium, Plasmodium, Babesia, Theileria, and Sarcocystis; parasites representing all branches of the apicomplexan phylogenetic tree. The compound also proved effective against Cryptosporidium parvum infection in neonatal mice, indicating that trtE may be a potential lead compound for preclinical development. Identification of a promising new compound after such limited screening strongly encourages further mining of invertebrate symbionts for new anti-parasitic therapeutics.

The free-living amebae Naegleria, Acanthamoeba, and Balamuthia cause rare but life-threatening infections. All three parasites can cause meningoencephalitis. Acanthamoeba can also cause chronic keratitis and both Balamuthia and Acanthamoeba can cause skin and systemic infections. There are minimal drug development pipelines for these pathogens despite a lack of available treatment regimens and high fatality rates. To identify anti-amebic drugs, we screened 159 compounds from a high-value repurposed library against trophozoites of the three amebae. Our efforts identified 38 compounds with activity against at least one ameba. Multiple drugs that bind the ATP-binding pocket of mTOR and PI3K are active, highlighting these compounds as important inhibitors of these parasites. Importantly, 24 active compounds have progressed at least to phase II clinical studies and overall 15 compounds were active against all three amebae. Based on central nervous system (CNS) penetration or exceptional potency against one amebic species, we identified sixteen priority compounds for the treatment of meningoencephalitis caused by these pathogens. The top five compounds are (i) plicamycin, active against all three free-living amebae and previously U.S. Food and Drug Administration (FDA) approved, (ii) TG02, active against all three amebae, (iii and iv) FDA-approved panobinostat and FDA orphan drug lestaurtinib, both highly potent against Naegleria, and (v) GDC-0084, a CNS penetrant mTOR inhibitor, active against at least two of the three amebae. These results set the stage for further investigation of these clinically advanced compounds for treatment of infections caused by the free-living amebae, including treatment of the highly fatal meningoencephalitis.

Herein, we report the preparation of a panel of Schiff bases analogues as antiprotozoal agents by modification of the stereoelectronic effects of the substituents on N-1 and N-4 and the nature of the chalcogen atom (S, Se). These compounds were evaluated towards Trypanosoma cruzi and Trichomonas vaginalis. Thiosemicarbazide 31 showed the best trypanocidal profile (epimastigotes), similar to benznidazole (BZ): IC50 (31)=28.72 μM (CL-B5 strain) and 33.65 μM (Y strain), IC50 (BZ)=25.31 μM (CL-B5) and 22.73 μM (Y); it lacked toxicity over mammalian cells (CC50 > 256 µM). Thiosemicarbazones 49, 51 and 63 showed remarkable trichomonacidal effects (IC50 =16.39, 14.84 and 14.89 µM) and no unspecific cytotoxicity towards Vero cells (CC50 ≥ 275 µM). Selenoisosters 74 and 75 presented a slightly enhanced activity (IC50=11.10 and 11.02 µM, respectively). Hydrogenosome membrane potential and structural changes were analysed to get more insight into the trichomonacidal mechanism.

Introduction: Leishmaniasis is a disease with high mortality rates and approximately 1.5 million new cases each year. Despite the new approaches and advances to fight the disease, there are no effective therapies. Methods: Hence, this study aims to screen for natural products' structural analogs as new drug candidates against leishmaniasis. We applied Computer-aided drug design (CADD) approaches, such as virtual screening, molecular docking, molecular dynamics simulation, molecular mechanics–generalized Born surface area (MM–GBSA) binding free estimation, and free energy perturbation (FEP) aiming to select structural analogs from natural products that have shown anti-leishmanial and anti-arginase activities and that could bind selectively against the Leishmania arginase enzyme. Results: The compounds 2H-1-benzopyran, 3,4-dihydro-2-(2-methylphenyl)-(9CI), echioidinin, and malvidin showed good results against arginase targets from three parasite species and negative results for potential toxicities. The echioidinin and malvidin ligands generated interactions in the active center at pH 2.0 conditions by MM-GBSA and FEP methods. Conclusions: This work suggests the potential anti-leishmanial activity of the compounds and thus can be further in vitro and in vivo experimentally validated.

Trypanosomiasis is an important but neglected tropical diseases which continues to cause morbidity and mortality on a large scale in sub-Saharan Africa. In the present study, the aqueous leaf extract, flavonoid fraction, and subfractions of the flavonoid from A. senegalensis leaves were evaluated for their antitrypanosomal activities, effects on some hematological parameters, and some liver-based enzymes in mice infected with Trypanosoma brucei brucei. Mice treated with aqueous extract at a concentration range of 100–400 mg kg bw exhibited parasite inhibition range between 66.08 and 73.09% while mice treated with the flavonoid fraction (50-200 mg/kg bw) exhibited higher parasite inhibition (83.37-86.38%). Mice treated with subfractions of the flavonoids showed a significant decrease in parasite count (p < 0.05), with subfraction 3 completely clearing parasites in the circulation after twenty-one days of treatment. Biochemical analysis revealed that the subfraction 3 restored the alterations in the serum aspartate transaminase (AST), alanine transaminase (ALT), and total protein concentrations that were observed in the infected nontreated mice. The subfraction 3 was subsequently characterized by HPLC analysis which revealed the presence of rutin (RT: 22.26, 65.34 ppm) as the most abundant bioactive compound that could be attributed to the bioactivity of the subfraction 3. Other polyphenolic compounds identified included gallic acid (RT: 4.39, 0.578 ppm), quercetin (RT: 37.27, 0.729 ppm), kaempferol (RT: 38.33, 1.52 ppm), and luteolin (RT; 39.173, 32.77 ppm). Taken together, subfraction 3 of the flavonoid fraction from of A. senegalensis demonstrated potent antitrypanosomal activities and therefore represents a reserve of bioactive metabolite worthy of further exploration for the treatment of trypanosomiasis. [ABSTRACT FROM AUTHOR]

Pimaricin is a small polyene macrolide antibiotic and has been broadly used as an antimycotic and antiprotozoal agent in both humans and foods. As a thioesterase in type‐I polyketide synthase, pimTE controls the 26‐m‐r macrolide main chain release in pimaricin biosynthesis. In this work, we sought to determine whether the 6‐m‐r hemiketal formation was linked to pimTE‐catalyzed 26‐m‐r lactonization. Compared to non‐hemiketal TEs, pimTE is characterized by an aspartic acid residue (D179) accessible to the U‐turn motif in the acyl‐enzyme intermediate. Both the covalent docking and molecular dynamics simulations demonstrate that the reactive conformations for macrocyclic lactonization are drastically promoted by the 6‐m‐r hemiketal. Moreover, the small‐model quantum mechanistic calculations suggest that protic residues can significantly accelerate the 6‐m‐r hemiketal cyclization. In addition, the post‐hemiketal molecular dynamic simulations demonstrate that hydrogen‐bonding networks surrounding the substrate U‐turn of the hairpin‐shaped conformation changes significantly when the 6‐m‐r hemiketal is formed. In particular, the R‐hemiketal intermediate is not only catalyzed by the D179 residue, but also twists the hairpin structure to the 26‐m‐r lactonizing pre‐reaction state. By contrast, the S‐hemiketal formation is unlikely catalyzed by D179, which twists the hairpin in an opposite direction. Our results propose that pimTE could be a bi‐functional enzyme, which can synergistically catalyze tandem 6‐m‐r and 26‐m‐r formations during the main‐chain release of pimaricin biosynthesis. [ABSTRACT FROM AUTHOR]