-
European Journal of Pharmacology Nov 2021Leishmaniasis is regarded as a neglected tropical disease by World Health Organization (WHO) and is ranked next to malaria as the deadliest protozoan disease. The... (Review)
Review
Leishmaniasis is regarded as a neglected tropical disease by World Health Organization (WHO) and is ranked next to malaria as the deadliest protozoan disease. The primary causative agents of the disease comprise of diverse leishmanial species sharing clinical features ranging from skin abrasions to lethal infection in the visceral organs. As several Leishmania species are involved in infection, the role of accurate diagnosis becomes pivotal in adding new dimensions to anti-leishmanial therapy. Diagnostic methods must be fast, reliable, easy to perform, highly sensitive, and specific to differentiate among similar parasitic diseases. Herein, we present the conventional and recent approaches impended for the disease diagnosis and their sensitivity, specificity, and clinical application in parasite detection. Furthermore, we have also elaborated various new methods to cure leishmaniasis, which include host-directed therapies, drug repurposing, nanotechnology, and combinational therapy. This review addresses novel techniques and innovations in leishmaniasis, which can aid in unraveling new strategies to fight against the deadly infection.
Topics: Amphotericin B; Animals; Antiprotozoal Agents; Diagnostic Techniques and Procedures; Humans; Leishmania; Leishmaniasis; Nanotechnology
PubMed: 34428435
DOI: 10.1016/j.ejphar.2021.174436 -
Current Topics in Medicinal Chemistry 2017Trichomoniasis is a sexually transmitted disease (STD) caused by infection with the protozoan parasite Trichomonas vaginalis. It is considered the most prevalent... (Review)
Review
Trichomoniasis is a sexually transmitted disease (STD) caused by infection with the protozoan parasite Trichomonas vaginalis. It is considered the most prevalent non-viral sexually transmitted disease worldwide. Recently, the infection has been associated with adverse outcomes of pregnancy and increased risks of HIV acquisition and transmission, as well as an association with cervical and prostate cancers. The consequences of trichomoniasis are likely much greater than previously recognized, both at the individual and the community level. Since many cases are asymptomatic, and the most common approach used for diagnosis (wet mount) is also one of the least sensitive, millions of T. vaginalis infections remain undiagnosed and therefore untreated. The purpose of this review is to address what is known about the treatment of T. vaginalis infections and what additional approaches could be pursued. The increasing recognition of the potential public health implications of trichomoniasis has resulted in greater attention to improving effectiveness of the interventions for affected individuals. Currently, treatment relies almost solely on one class of drugs, the 5- nitroimidazoles, which causes concern should widespread drug resistance arise. There are also concerns regarding which 5-nitroimidazole to use as not all of them are active against T. vaginalis. Finally, new therapeutic targets and active compounds with treatment potential are considered.
Topics: Animals; Antiprotozoal Agents; Humans; Molecular Structure; Parasitic Sensitivity Tests; Trichomonas Infections; Trichomonas vaginalis
PubMed: 27697044
DOI: 10.2174/1568026616666160930150429 -
Journal of Natural Products Dec 2018Fractionation of the n-hexane extract of Salvia hydrangea afforded seven isoprenoids including six new compounds (1-6) and salvadione A (7). Their structures were...
Fractionation of the n-hexane extract of Salvia hydrangea afforded seven isoprenoids including six new compounds (1-6) and salvadione A (7). Their structures were established by comprehensive spectroscopic and spectrometric data analysis (1D and 2D NMR, HRMS). The absolute configuration of salvadione A (7) was established by single-crystal X-ray diffraction analysis with Cu/Kα radiation. In addition, the absolute configuration of all compounds was determined by electronic circular dichroism spectroscopy. A biosynthetic pathway for the formation of the scaffold of 1 is proposed. The antiprotozoal activity of the compounds against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum was determined, and cytotoxicity was assessed in rat myoblast L6 cells. Perovskone C (2) exhibited good activity against P. falciparum (IC 0.6 μM) and a selectivity index of 62.2.
Topics: Animals; Antiprotozoal Agents; Cell Line; Leishmania donovani; Magnetic Resonance Spectroscopy; Molecular Structure; Plasmodium falciparum; Rats; Salvia; Spectrum Analysis; Terpenes; Trypanosoma brucei rhodesiense; Trypanosoma cruzi
PubMed: 30565934
DOI: 10.1021/acs.jnatprod.8b00498 -
Bioorganic Chemistry Dec 2023Trichomonas vaginalis, a flagellated and anaerobic protozoan, is a causative agent of trichomoniasis. This disease is among the world's most common non-viral sexually...
Trichomonas vaginalis, a flagellated and anaerobic protozoan, is a causative agent of trichomoniasis. This disease is among the world's most common non-viral sexually transmitted infection. A single class drug, nitroimidazoles, is currently available for the trichomoniasis treatment. However, resistant isolates have been identified from unsuccessfully treated patients. Thus, there is a great challenge for a discovery of innovative anti-T. vaginalis agents. As part of our ongoing search for antiprotozoal chalcones, we designed and synthesized a series of 21 phenolic chalcones, which were evaluated against T. vaginalis trophozoites. Structure-activity relationship indicated hydroxyl group plays a role key in antiprotozoal activity. 4'-Hydroxychalcone (4HC) was the most active compound (IC = 27.5 µM) and selected for detailed bioassays. In vitro and in vivo evaluations demonstrated 4HC was not toxic against human erythrocytes and Galleria mellonella larvae. Trophozoites of T. vaginalis were treated with 4HC and did not present significant reactive oxygen species (ROS) accumulation. However, compound 4HC was able to increase ROS accumulation in neutrophils coincubated with T. vaginalis. qRT-PCR Experiments indicated that 4HC did not affect the expression of pyruvate:ferredoxin oxidoreductase (PFOR) and β-tubulin genes. In silico simulations, using purine nucleoside phosphorylase of T. vaginalis (TvPNP), corroborated 4HC as a promising ligand. Compound 4HC was able to establish interactions with residues D21, G20, M180, R28, R87 and T90 through hydrophobic interactions, π-donor hydrogen bond and hydrogen bonds. Altogether, these results open new avenues for phenolic chalcones to combat trichomoniasis, a parasitic neglected infection.
Topics: Humans; Trichomonas vaginalis; Chalcones; Reactive Oxygen Species; Trichomonas Infections; Antiprotozoal Agents; Phenols
PubMed: 37839143
DOI: 10.1016/j.bioorg.2023.106888 -
European Journal of Medicinal Chemistry Dec 2018Leishmaniasis affects over 150 million people all over the world, especially in subtropical regions. Currently used antileishmanial synthesized drugs are associated with... (Review)
Review
Leishmaniasis affects over 150 million people all over the world, especially in subtropical regions. Currently used antileishmanial synthesized drugs are associated with some drawbacks such as resistance and cytotoxicity, which hamper the chances of treatment. Furthermore, effective leishmanial vaccines are not well developed. Promising chemotherapy, either from natural or synthetic compounds, was or still is the most promising treatment. This review focuses on recent findings in drugs used for the treatment of leishmaniasis including; chemical and natural antileishmanial moieties, different potential targets, as well as various trials of vaccination development. Special emphasis has been paid to the mechanisms of the drugs, their safety and where possible, the structure-activity relationship to enable guided future drug discovery.
Topics: Animals; Antiprotozoal Agents; Biological Products; Dose-Response Relationship, Drug; Drug Discovery; Humans; Leishmania; Molecular Structure; Structure-Activity Relationship
PubMed: 30342363
DOI: 10.1016/j.ejmech.2018.10.022 -
International Immunopharmacology Jan 2023Leishmaniasis, a tropically neglected disease, is responsible for the high mortality and morbidity ratio in poverty-stricken areas. Currently, no vaccine is available... (Review)
Review
Leishmaniasis, a tropically neglected disease, is responsible for the high mortality and morbidity ratio in poverty-stricken areas. Currently, no vaccine is available for the complete cure of the disease. Current chemotherapeutic regimens face the limitations of drug resistance and toxicity concerns indicating a great need to develop better chemotherapeutic leads that are orally administrable, potent, non-toxic, and cost-effective. The anti-leishmanial drug discovery process accelerated the desire for large-scale drug screening assays and high-throughput screening (HTS) technology to identify new chemo-types that can be used as potential drug molecules to control infection. Using the HTS approach, about one million compounds can be screened daily within the shortest possible time for biological activity using automation tools, miniaturized assay formats, and large-scale data analysis. Classical and modern in vitro screening assays have led to the progression of active compounds further to ex vivo and in vivo studies. In the present review, we emphasized on the HTS approaches employed in the leishmanial drug discovery program. Recent in vitro screening assays are widely explored to discover new chemical scaffolds. Developing appropriate experimental animal models and their related techniques is necessary to understand the pathophysiological processes and disease host responses, paving the way for unraveling novel therapies against leishmaniasis.
Topics: Animals; Drug Evaluation, Preclinical; Antiprotozoal Agents; Leishmaniasis; Leishmania; High-Throughput Screening Assays
PubMed: 36700771
DOI: 10.1016/j.intimp.2022.109591 -
Mini Reviews in Medicinal Chemistry 2023Leishmaniases are infectious diseases caused by flagellated protozoan parasites belonging to the genus that infect cells of the mononuclear phagocytic system. These... (Review)
Review
Leishmaniases are infectious diseases caused by flagellated protozoan parasites belonging to the genus that infect cells of the mononuclear phagocytic system. These parasites are transmitted to humans by biting an infected female sandfly belonging to the genera in the Old World and in the New World. Despite representing a major public health problem, the therapeutic options are old and have several disadvantages. Given this scenario, developing vaccines or drugs for oral administration is necessary. Therefore, integrating computational and experimental strategies into the studies on molecular targets essential for the survival and virulence of the parasite is fundamental in researching and developing new treatments for leishmaniasis. In the effort to develop new vaccines and drugs, molecular docking methods are widely used as they explore the adopted conformations of small molecules within the binding sites of macromolecular targets and estimate the free energy of target-ligand binding. Privileged structures have been widely used as an effective model in medicinal chemistry for drug discovery. Chalcones are a common simple scaffold found in many compounds of natural and synthetic origin, where studies demonstrate the great pharmacological potential in treating leishmaniasis. This review is based on scientific articles published in the last ten years on molecular docking of chalcone derivatives for essential molecular targets of . Thus, this review emphasizes how versatile chalcone derivatives can be used in developing new inhibitors of important molecular targets involved in the survival, growth, cell differentiation, and infectivity of the parasites that cause leishmaniasis.
Topics: Female; Humans; Chalcones; Chalcone; Molecular Docking Simulation; Antiprotozoal Agents; Leishmania; Leishmaniasis; Drug Discovery
PubMed: 36705240
DOI: 10.2174/1389557523666230127125058 -
Chemistry & Biodiversity Sep 2019The natural polyisoprenylated benzophenone derivatives garcinol and isogarcinol are secondary plant metabolites isolated from various Garcinia species including Garcinia... (Review)
Review
The natural polyisoprenylated benzophenone derivatives garcinol and isogarcinol are secondary plant metabolites isolated from various Garcinia species including Garcinia indica. This review takes stock of the recent chemical and biological research into these interesting natural compounds over the last five years. New biological sources and chemical syntheses are discussed followed by new insights into the activity of garcinol and isogarcinol against cancer, pathogenic bacteria, parasite infections and various inflammatory diseases.
Topics: Animals; Anti-Infective Agents; Antineoplastic Agents, Phytogenic; Antiprotozoal Agents; Garcinia; Humans; Neoplasms; Terpenes
PubMed: 31386266
DOI: 10.1002/cbdv.201900366 -
PloS One 2020The plenteous resistance to and undesirable consequences of the existing antipiroplasmic therapies have emphasized the urgent need for new chemotherapeutics and drug...
BACKGROUND
The plenteous resistance to and undesirable consequences of the existing antipiroplasmic therapies have emphasized the urgent need for new chemotherapeutics and drug targets for both prophylaxis and chemotherapy. Hydroxyurea (HYD) is an antineoplastic agent with antitrypanosomal activity. Eflornithine (α-difluoro-methyl ornithine, DFMO) is the best choice therapy for the treatment of late-stage Gambian human African trypanosomiasis.
METHODS
In this study, the inhibitory and combination efficacy of HYD and DFMO with existing babesicidal drugs (diminazene aceturate (DA), atovaquone (ATV), and clofazimine (CLF)) deoxyribonucleotide in vitro against the multiplication of Babesia and Theileria. As well as, their chemotherapeutic effects were assessed on B. microti strain that infects rodents. The Cell Counting Kits-8 (CCK-8) test was used to examine their cytotoxicity on human foreskin fibroblast (HFF), mouse embryonic fibroblast (NIH/3T3), and Madin-Darby bovine kidney (MDBK) cells.
FINDINGS
HYD and DFMO suppressed the multiplication of all tested species (B. bigemina, B. bovis, B. caballi, B. divergens, and T. equi) in a dose-related manner. HFF, NIH/3T3, or MDBK cell viability was not influenced by DFMO at 1000 μM, while HYD affected the MDBK cell viability at EC50 value of 887.5±14.4 μM. The in vitro combination treatments of DFMO and HYD with CLF, DA, and ATV exhibited synergistic and additive efficacy toward all tested species. The in vivo experiment revealed that HYD and DFMO oral administration at 100 and 50 mg/kg inhibited B. microti multiplication in mice by 60.1% and 78.2%, respectively. HYD-DA and DFMO-DA combined treatments showed higher chemotherapeutic efficacy than their monotherapies.
CONCLUSION
These results indicate the prospects of HYD and DFMO as drug candidates for piroplasmosis treatment, when combined mainly with DA, ATV, and CLF. Therefore, further studies are needed to combine HYD or DFMO with either ATV or CLF and examine their impact on B. microti infection in mice.
Topics: Animals; Antineoplastic Agents; Antiprotozoal Agents; Atovaquone; Babesia; Cell Survival; Clofazimine; Diminazene; Dogs; Eflornithine; Foreskin; Humans; Hydroxyurea; Male; Mice; NIH 3T3 Cells; Theileria
PubMed: 32053698
DOI: 10.1371/journal.pone.0228996 -
Expert Opinion on Drug Metabolism &... Jul 2019: Being on the top list of neglected tropical diseases, leishmaniasis has been marked for elimination by 2020. In the light of small armamentarium of drugs and their... (Review)
Review
: Being on the top list of neglected tropical diseases, leishmaniasis has been marked for elimination by 2020. In the light of small armamentarium of drugs and their associated drawbacks, the understanding of pharmacodynamics and/or pharmacokinetics becomes a priority to achieve and sustain disease elimination. : The authors have looked into pharmacological aspects of existing and emerging drugs for treatment of leishmaniasis. An in-depth understanding of pharmacodynamics and pharmacokinetics (PKPD) provides a rationale for drug designing and optimizing the treatment strategies. It forms a key to prevent drug resistance and avoid drug-associated adverse effects. The authors have compiled the researches on the PKPD of different anti-leishmanial formulations that have the potential for improved and/or effective disease intervention. : Understanding the pharmacological aspects of drugs forms the basis for the clinical application of novel drugs. Tailoring drug dosage and individualized treatment can avoid the adverse events and bridge gap between the models and their clinical application. An integrated approach, with pragmatic use of technological advances can improve phenotypic screening and physiochemical properties of novel drugs. Concomitantly, this can serve to improve clinical efficacies, reduce the incidence of relapse and accelerate the drug discovery/development process for leishmaniasis elimination.
Topics: Animals; Antiprotozoal Agents; Dose-Response Relationship, Drug; Drug Design; Drug Development; Drug Discovery; Drug Resistance; Humans; Leishmaniasis
PubMed: 31174439
DOI: 10.1080/17425255.2019.1629417