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Molecules (Basel, Switzerland) Mar 2024Over the years, several new medicinal substances have been introduced for the treatment of diseases caused by bacteria and parasites. Unfortunately, due to the...
Over the years, several new medicinal substances have been introduced for the treatment of diseases caused by bacteria and parasites. Unfortunately, due to the production of numerous defense mechanisms by microorganisms and parasites, they still pose a serious threat to humanity around the world. Therefore, laboratories all over the world are still working on finding new, effective methods of pharmacotherapy. This research work aimed to synthesize new compounds derived from 3-trifluoromethylbenzoic acid hydrazide and to determine their biological activity. The first stage of the research was to obtain seven new compounds, including six linear compounds and one derivative of 1,2,4-triazole. The PASS software was used to estimate the potential probabilities of biological activity of the newly obtained derivatives. Next, studies were carried out to determine the nematocidal potential of the compounds with the use of nematodes of the genus sp. and antibacterial activity using the ACCT standard strains. To determine the lack of cytotoxicity, tests were performed on two cell lines. Additionally, an antioxidant activity test was performed due to the importance of scavenging free radicals in infections with pathogenic microorganisms. The conducted research proved the anthelmintic and antibacterial potential of the newly obtained compounds. The most effective were two compounds with a 3-chlorophenyl substituent, both linear and cyclic derivatives. They demonstrated higher efficacy than the drugs used in treatment.
Topics: Anti-Bacterial Agents; Antinematodal Agents; Cell Line; Hydrazines; Semicarbazides
PubMed: 38611813
DOI: 10.3390/molecules29071529 -
Journal of Medicinal Chemistry Nov 2023Broad-spectrum anti-infective chemotherapy agents with activity against , and species were identified from a high-throughput phenotypic screening program of the 456...
Broad-spectrum anti-infective chemotherapy agents with activity against , and species were identified from a high-throughput phenotypic screening program of the 456 compounds belonging to the Ty-Box, an in-house industry database. Compound characterization using machine learning approaches enabled the identification and synthesis of 44 compounds with broad-spectrum antiparasitic activity and minimal toxicity against , and . In vitro studies confirmed the predictive models identified in compound which emerged as a new lead, featured by an innovative -(5-pyrimidinyl)benzenesulfonamide scaffold and promising low micromolar activity against two parasites and low toxicity. Given the volume and complexity of data generated by the diverse high-throughput screening assays performed on the compounds of the Ty-Box library, the chemoinformatic and machine learning tools enabled the selection of compounds eligible for further evaluation of their biological and toxicological activities and aided in the decision-making process toward the design and optimization of the identified lead.
Topics: High-Throughput Screening Assays; Antiparasitic Agents; Trypanosoma cruzi; Trypanosoma brucei brucei; Leishmania infantum
PubMed: 37921561
DOI: 10.1021/acs.jmedchem.3c01322 -
Acta Pharmaceutica (Zagreb, Croatia) Dec 2023Here we present the synthesis and evaluation of the biological activity of new hybrid compounds, ureido-type (UT) harmiquins, based on chloroquine (CQ) or mefloquine...
Here we present the synthesis and evaluation of the biological activity of new hybrid compounds, ureido-type (UT) harmiquins, based on chloroquine (CQ) or mefloquine (MQ) scaffolds and β-carboline alkaloid harmine against cancer cell lines and . The hybrids were prepared from the corresponding amines by 1,1'-carbonyldiimidazole (CDI)-mediated synthesis. evaluation of the biological activity of the title compounds revealed two hit compounds. Testing of the antiproliferative activity of the new UT harmiquins, and previously prepared triazole-(TT) and amide-type (AT) CQ-based harmiquins, against a panel of human cell lines, revealed TT harmiquine as the most promising compound, as it showed pronounced and selective activity against the tumor cell line HepG2 ( = 5.48 ± 3.35 μmol L). Screening of the antiplasmodial activities of UT harmiquins against erythrocytic stages of the life cycle identified CQ-based UT harmiquine as a novel antiplasmodial hit because it displayed low values in the submicromolar range against CQ-sensitive and resistant strains ( 0.06 ± 0.01, and 0.19 ± 0.02 μmol L, respectively), and exhibited high selectivity against , compared to mammalian cells (SI = 92).
Topics: Humans; Antimalarials; Cell Line, Tumor; Chloroquine; Mefloquine; Parasitic Sensitivity Tests
PubMed: 38147482
DOI: 10.2478/acph-2023-0035 -
Pathogens and Global Health Oct 2023Praziquantel (PZQ) has been extensively used as the drug of choice for the treatment of schistosomiasis on account of its safety and effectiveness against all major...
Praziquantel (PZQ) has been extensively used as the drug of choice for the treatment of schistosomiasis on account of its safety and effectiveness against all major forms of schistosomiasis. However, low cure rate, reduced susceptibility of to PZQ and treatment failures in . infections have been reported, raising concerns about its efficacy. Using the search terms, 'praziquantel efficacy, schistosomiasis, school children, reinfection' as well as defined inclusion criteria, and guided by the PRISMA guidelines, articles from 2001 to 2022 were selected from the PubMed and Google Scholar databases and reviewed to assess their importance to the research question. This review assessed the efficacy of PZQ against schistosomiasis and reinfection rates following treatment of infections in children. Majority of both intestinal and urinary schistosomiasis studies reported comparable egg reduction rates (ERRs) of 94.2% to 99.9% and 91.9% to 98%, respectively. However, ERRs suggestive of sub-optimal PZQ efficacy as well as generally high and comparable cure rates for intestinal (81.2%-99.1%) and urinary (79%-93.7%) schistosomiasis studies were reported. Schistosomiasis reinfection rates varied widely for urinary (8.1%-39.6%) and intestinal (13.9%-63.4%) studies within eight to 28 weeks following PZQ treatment. Praziquantel treatment of urinary and intestinal schistosomiasis should be accompanied by the provision of potable water, toilet, and recreational facilities to reduce reinfection and egg reduction rates and increase cure rate to expedite schistosomiasis elimination.
Topics: Child; Humans; Praziquantel; Schistosomiasis mansoni; Anthelmintics; Reinfection; Treatment Outcome; Schistosomiasis haematobia
PubMed: 36394218
DOI: 10.1080/20477724.2022.2145070 -
International Journal For Parasitology.... Aug 2023Reports of anthelmintic resistance in Ancylostoma caninum are increasing in frequency in the United States of America (USA). In the last few years in vitro and in vivo... (Review)
Review
Reports of anthelmintic resistance in Ancylostoma caninum are increasing in frequency in the United States of America (USA). In the last few years in vitro and in vivo studies characterized individual isolates, demonstrating multiple anthelmintic drug resistance (MADR). In 2021, the American Association of Veterinary Parasitologists initiated a hookworm task force to address this issue. The first report of drug resistant A. caninum occurred in 1987 in Australian racing Greyhounds. In the last five years multiple case reports and investigations show drug resistant A. caninum is becoming a much greater problem in the USA and now extends beyond racing Greyhounds into the general companion animal dog population. The literature, regarding drug resistance in livestock and equine nematodes, provides helpful guidance along with diagnostic methods to better understand the evolution and selection of canine MADR hookworms; however, there are limitations and caveats due to A. caninum's unique biology and zoonotic potential. Mass drug administration (MDA) of anthelminthic drugs to humans to reduce morbidity associated with human hookworms (Necator americanus) should consider the factors that contributed to the development of MADR A. caninum. Finally, as Greyhound racing undergoes termination in some regions and the retired dogs undergo subsequent rehoming, drug resistant parasites, if present, are carried with them. Drug resistant A. caninum requires greater recognition by the veterinary community, and small animal practitioners need to be aware of the spread into current pet dog populations. The current understanding of anthelmintic resistance, available treatments, and environmental mitigation for these drug resistant A. caninum isolates must be monitored for horizontal spread. A major goal in this emerging problem is to prevent continued dissemination.
Topics: Animals; Dogs; Horses; Humans; Ancylostoma; Ancylostomiasis; Dog Diseases; Australia; Anthelmintics; Ancylostomatoidea
PubMed: 37229949
DOI: 10.1016/j.ijpddr.2023.04.003 -
International Journal For Parasitology.... Aug 2023Anoplocephalid tapeworms are commonly occurring in grazing horses around the world. Two currently available anthelmintics have documented high efficacy against...
Anoplocephalid tapeworms are commonly occurring in grazing horses around the world. Two currently available anthelmintics have documented high efficacy against Anoplocephala perfoliata; praziquantel in various dosages ranging from 1.0 to 2.5 mg/kg and pyrantel pamoate administered at 13.2 mg base/kg. Anthelmintic resistance has not been reported in A. perfoliata, but anecdotal reports made during 2022 have suggested a possible loss of efficacy for both actives. This paper reports fecal egg count data from a Thoroughbred operation in Central Kentucky in 2023. Fifty-six yearlings were first dewormed with a combination of ivermectin (200 μg/kg) and praziquantel (1.5 mg/kg) and subsequently treated with pyrantel pamoate (13.2 mg base/kg). Fecal egg counts were determined at the day of treatment and again 14 days post-treatment. Two groups of mares (n = 39 and 45) were also treated with ivermectin/praziquantel and examined pre- and post-treatment. Low efficacy of ivermectin and pyrantel pamoate was demonstrated against strongylid parasites in the yearlings with mean Fecal Egg Count Reductions (FECRs) at 75.6% or below and upper 95% credible interval (CI) limits below 90% in all cases. Overall anti-cestodal FECR levels in the yearlings were 23.5% (95% CI: 11.2-48.0) for praziquantel and 50.9% (20.5-72.0) for pyrantel pamoate. Praziquantel eliminated anoplocephalid eggs from three of 17 yearlings, but another 5 yearlings went from negative to positive status following treatment. Pyrantel pamoate failed to eliminate anoplocephalid eggs from any of 14 treated tapeworm-positive yearlings. Nine of 84 mares tested positive for anoplocephalid eggs, and seven of these were still positive post praziquantel treatment. These findings sharply contrast data from historic field efficacy studies conducted for both actives and raise concern about anthelmintic resistance having possibly developed. This emphasizes the need for developing and refining antemortem methodologies for evaluating anti-cestodal treatment efficacy and for searching for possible alternative treatment options.
Topics: Animals; Horses; Female; Pyrantel Pamoate; Praziquantel; Ivermectin; Horse Diseases; Anthelmintics; Cestoda; Treatment Failure; Feces; Treatment Outcome; Parasite Egg Count
PubMed: 37354849
DOI: 10.1016/j.ijpddr.2023.06.002 -
Molecules (Basel, Switzerland) Oct 2023and sp. resistance to antiparasitic drugs has become a major concern in malaria and leishmaniasis control. These diseases are public health problems with significant...
and sp. resistance to antiparasitic drugs has become a major concern in malaria and leishmaniasis control. These diseases are public health problems with significant socioeconomic impacts, and mostly affect disadvantaged populations living in remote tropical areas. This challenge emphasizes the need to search for new chemical scaffolds that preferably possess novel modes of action to contribute to antimalarial and antileishmanial research programs. This study aimed to investigate the antimalarial and antileishmanial properties of a methanol extract (-) of the stem bark of the Cameroonian medicinal plant and its isolated compounds. The purification of - led to the isolation of a new ordered limonoid derivative, 21-hydroxybourjotinolone A (), together with 15 known compounds (-) using a repeated column chromatography. Compound was obtained in an epimeric mixture of 21-melianodiol () and 21-melianodiol (). Structural characterization of the isolated compounds was achieved with HRMS, and 1D- and 2D-NMR analyses. The extracts and compounds were screened using pre-established in vitro methods against synchronized ring stage cultures of the multidrug-resistant Dd2 and chloroquine-sensitive/sulfadoxine-resistant 3D7 strains of and the promastigote form of (1S(MHOM/SD/62/1S). In addition, the samples were tested for cytotoxicity against RAW 264.7 macrophages. Positive controls consisted of artemisinin and chloroquine for , amphotericin B for , and podophyllotoxin for cytotoxicity against RAW 264.7 cells. The extract and fractions exhibited moderate to potent antileishmanial activity with 50% inhibitory concentrations (IC) ranging from 5.99 ± 0.77 to 2.68 ± 0.42 μg/mL, while compounds displayed IC values ranging from 81.73 ± 0.12 to 6.43 ± 0.06 μg/mL. They were weakly active against the chloroquine-sensitive/sulfadoxine-resistant 3D7 strain but highly potent toward the multidrug-resistant Dd2 (extracts, IC 2.50 ± 0.12 to 4.78 ± 0.36 μg/mL; compounds IC 2.93 ± 0.02 to 50.97 ± 0.37 μg/mL) with selectivity indices greater than 10 (SI > 10) for the extract and fractions and most of the derived compounds. Of note, the limonoid mixture [21-hydroxylbourjotinolone A () + 21-melianodiol () + 21-melianodiol ()] exhibited moderate activity against and This novel antiplasmodial and antileishmanial chemical scaffold qualifies as a promising starting point for further medicinal chemistry-driven development of a dually active agent against two major infectious diseases affecting humans in Africa.
Topics: Humans; Antimalarials; Limonins; Plant Extracts; Sulfadoxine; Plant Bark; Antiprotozoal Agents; Chloroquine; Malaria, Falciparum; Meliaceae; Plasmodium falciparum
PubMed: 37894704
DOI: 10.3390/molecules28207227 -
PLoS Neglected Tropical Diseases Feb 2024The drug praziquantel (PZQ) has served as the long-standing drug therapy for treatment of infections caused by parasitic flatworms. These encompass diseases caused by... (Review)
Review
The drug praziquantel (PZQ) has served as the long-standing drug therapy for treatment of infections caused by parasitic flatworms. These encompass diseases caused by parasitic blood, lung, and liver flukes, as well as various tapeworm infections. Despite a history of clinical usage spanning over 4 decades, the parasite target of PZQ has long resisted identification. However, a flatworm transient receptor potential ion channel from the melastatin subfamily (TRPMPZQ) was recently identified as a target for PZQ action. Here, recent experimental progress interrogating TRPMPZQ is evaluated, encompassing biochemical, pharmacological, genetic, and comparative phylogenetic data that highlight the properties of this ion channel. Various lines of evidence that support TRPMPZQ being the therapeutic target of PZQ are presented, together with additional priorities for further research into the mechanism of action of this important clinical drug.
Topics: Praziquantel; Anthelmintics; Phylogeny; Transient Receptor Potential Channels
PubMed: 38358948
DOI: 10.1371/journal.pntd.0011929 -
Malaria Journal Oct 2023This study investigates the processes regarding changing malaria treatment policies in Vietnam. Moreover, it explores the feasibility of introducing triple... (Review)
Review
BACKGROUND
This study investigates the processes regarding changing malaria treatment policies in Vietnam. Moreover, it explores the feasibility of introducing triple artemisinin-based combination therapy (TACT) in Vietnam to support the national malaria control and elimination plan.
METHODS
Data were collected via 12 in-depth interviews with key stakeholders, combined with a review of policy documents.
RESULTS
TACT is considered as a useful backup strategy in case future treatment failures with current artemisinin-based combination therapy (ACT) would occur. Moreover, TACT is also considered as a promising strategy to prevent the re-establishment of malaria. However, regulatory procedures and implementation timelines for TACT were expected to be lengthy. Therefore, strategies to engage national decision-makers, regulators, and suppliers should be initiated soon, stipulating the benefits of TACT deployment. In Vietnam, a procedure to apply for an import permit without registration that has previously been applied to the introduction of artesunate-pyronaridine was proposed to accelerate the introduction of TACT. Global-level support through the World Health Organization recommendations and prequalification were considered critical for supporting the introduction of TACT in Vietnam.
CONCLUSIONS
Appropriate approach strategies and early stakeholder engagement will be needed to accelerate the introduction of TACT in Vietnam.
Topics: Humans; Antimalarials; Malaria, Falciparum; Vietnam; Feasibility Studies; Plasmodium falciparum; Artemisinins; Malaria; Drug Therapy, Combination; Policy
PubMed: 37898749
DOI: 10.1186/s12936-023-04763-4 -
Biomedicine & Pharmacotherapy =... Aug 2023Leishmaniasis and Chagas disease, two of the most prevalent neglected tropical diseases, are a world health problem. The harsh reality of these infective diseases is the...
Leishmaniasis and Chagas disease, two of the most prevalent neglected tropical diseases, are a world health problem. The harsh reality of these infective diseases is the absence of effective and safe therapies. In this framework, natural products play an important role in overcoming the current need to development new antiparasitic agents. The present study reports the synthesis, antikinetoplastid screening, mechanism study of fourteen withaferin A derivatives (2-15). Nine of them (2-6, 8-10 and 12) showed a potent dose-dependent inhibitory effect on the proliferation of Leishmania amazonensis and L. donovani promastigotes and Trypanosoma cruzi epimastigotes with IC values ranging from 0.19 to 24.01 µM. Outstandingly, the fully acetylated derivative 10 (4,27-diacetylwithaferin A) was the most potent compound showing IC values of 0.36, 2.82 and 0.19 µM against L. amazonensis, L. donovani and T. cruzi, respectively. Furthermore, analogue 10 exhibited approximately 18 and 36-fold greater antikinetoplastid activity, on L. amazonensis and T. cruzi, than the reference drugs. The activity was accompanied by significantly lower cytotoxicity on the murine macrophage cell line. Moreover, compounds 2, 3, 5-7, 9 and 10 showed more potent activity than the reference drug against the intracellular amastigotes forms of L. amazonensis and T.cruzi, with a good selectivity index on a mammalian cell line. In addition, withaferin A analogues 3, 5-7, 9 and 10 induce programmed cell death through a process of apoptosis-like and autophagy. These results strengthen the anti-parasitic potential of withaferin A-related steroids against neglected tropical diseases caused by Leishmania spp. and T. cruzi parasites.
Topics: Animals; Mice; Antiprotozoal Agents; Parasitic Sensitivity Tests; Leishmania; Chagas Disease; Apoptosis; Mammals
PubMed: 37210899
DOI: 10.1016/j.biopha.2023.114879