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Antimicrobial Agents and Chemotherapy May 2002
Review
Topics: Animals; Antifungal Agents; Antiprotozoal Agents; Atovaquone; Babesia; Humans; Naphthoquinones; Plasmodium; Pneumocystis; Pneumonia, Pneumocystis; Protozoan Infections; Randomized Controlled Trials as Topic; Toxoplasma
PubMed: 11959541
DOI: 10.1128/AAC.46.5.1163-1173.2002 -
Clinical Microbiology Reviews Jan 2001The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are... (Review)
Review
The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract, fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent, and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined. Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently been investigated using laboratory-induced resistant isolates. Instead of downregulation of the pyruvate:ferredoxin oxidoreductase and ferredoxin pathway as seen in G. duodenalis and T. vaginalis, E. histolytica induces oxidative stress mechanisms, including superoxide dismutase and peroxiredoxin. The review examines the value of investigating both clinical and laboratory-induced syngeneic drug-resistant isolates and dissection of the complementary data obtained. Comparison of resistance mechanisms in anaerobic bacteria and the parasitic protozoa is discussed as well as the value of studies of the epidemiology of resistance.
Topics: Anaerobiosis; Animals; Antiprotozoal Agents; Drug Resistance; Entamoeba histolytica; Entamoebiasis; Female; Giardia; Giardiasis; Humans; Male; Trichomonas Vaginitis; Trichomonas vaginalis
PubMed: 11148007
DOI: 10.1128/CMR.14.1.150-164.2001 -
Chirality Oct 2022Parasitic diseases, including malaria, leishmaniasis, and trypanosomiasis, affect billions of people and are responsible for almost 500,000 deaths/year. In particular,... (Review)
Review
Parasitic diseases, including malaria, leishmaniasis, and trypanosomiasis, affect billions of people and are responsible for almost 500,000 deaths/year. In particular, leishmaniasis, a neglected tropical disease, is considered a global public health problem because current drugs have several drawbacks including to toxicity, high cost, and drug resistance, which result in a lack of effective and readily available therapies. Therefore, the synthesis of new, safe, and effective molecules still requires the attention of the scientific community. Moreover, it is well known that chirality plays a crucial role in the antiparasitic activity of molecules, driving the design of their synthesis. Therefore, in this review we report a recent update on new chiral compounds with promising antileishmanial activity, focusing on synthetic approaches. Where reported, in most cases the enantiopure compound has shown better potency against the protozoa than its enantiomer or corresponding racemic mixture.
Topics: Antiprotozoal Agents; Humans; Leishmaniasis; Stereoisomerism
PubMed: 35947400
DOI: 10.1002/chir.23494 -
Molecules (Basel, Switzerland) Apr 2021Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole...
Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan's cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against , , and had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR.
Topics: Antiprotozoal Agents; Cheminformatics; Entamoeba histolytica; Giardia lamblia; Indazoles; Inhibitory Concentration 50; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trichomonas vaginalis; Ultrasonics
PubMed: 33917871
DOI: 10.3390/molecules26082145 -
Molecules (Basel, Switzerland) Feb 2021Betulinic acid (BA, 3β-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in ssp. (Betulaceae) and is also widely spread in many... (Review)
Review
Betulinic acid (BA, 3β-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in ssp. (Betulaceae) and is also widely spread in many species belonging to different plant families. BA presents a wide spectrum of remarkable pharmacological properties, such as cytotoxic, anti-HIV, anti-inflammatory, antidiabetic and antimicrobial activities, including antiprotozoal effects. The present review first describes the sources of BA and discusses the chemical strategies to produce this molecule starting from betulin, its natural precursor. Next, the antiprotozoal properties of BA are briefly discussed and the chemical strategies for the synthesis of analogues displaying antiplasmodial, antileishmanial and antitrypanosomal activities are systematically presented. The antiplasmodial activity described for BA was moderate, nevertheless, some C-3 position acylated analogues showed an improvement of this activity and the hybrid models-with artesunic acid-showed the most interesting properties. Some analogues also presented more intense antileishmanial activities compared with BA, and, in addition to these, heterocycles fused to C-2/C-3 positions and amide derivatives were the most promising analogues. Regarding the antitrypanosomal activity, some interesting antitrypanosomal derivatives were prepared by amide formation at the C-28 carboxylic group of the lupane skeleton. Considering that BA can be produced either by isolation of different plant extracts or by chemical transformation of betulin, easily obtained from ssp., it could be said that BA is a molecule of great interest as a starting material for the synthesis of novel antiprotozoal agents.
Topics: Antiprotozoal Agents; Models, Molecular; Pentacyclic Triterpenes; Triterpenes; Betulinic Acid
PubMed: 33670791
DOI: 10.3390/molecules26041081 -
Clinical Microbiology Reviews Jul 2017The last estimated annual incidence of worldwide exceeds that of chlamydia and gonorrhea combined. This critical review updates the state of the art on advances in... (Review)
Review
The last estimated annual incidence of worldwide exceeds that of chlamydia and gonorrhea combined. This critical review updates the state of the art on advances in diagnostics and strategies for treatment and prevention of trichomoniasis. In particular, new data on treatment outcomes for topical administration of formulations are reviewed and discussed.
Topics: Administration, Topical; Antiprotozoal Agents; Humans; Trichomonas Infections; Trichomonas vaginalis
PubMed: 28539504
DOI: 10.1128/CMR.00109-16 -
Frontiers in Cellular and Infection... 2023Leishmaniasis is a neglected tropical disease with a wide spectrum of clinical manifestations, ranging from visceral to cutaneous, with millions of new cases and... (Review)
Review
Leishmaniasis is a neglected tropical disease with a wide spectrum of clinical manifestations, ranging from visceral to cutaneous, with millions of new cases and thousands of deaths reported each year. The species of and the immune response of the host determine the severity of the disease. Leishmaniasis remains challenging to diagnose and treat, and there is no vaccine available. Several studies have been conducted on the use of herbal medicines for the treatment of leishmaniasis. Natural products can provide an inexhaustible source of chemical diversity with therapeutic potential. Terpenes are a class of natural products derived from a single isoprene unit, a five-carbon compound that forms the basic structure of isoprenoids. This review focuses on the most important and recent advances in the treatment of parasites of the genus with different subclasses of terpenes. Several mechanisms have been proposed in the literature, including increased oxidative stress, immunomodulatory role, and induction of different types of parasite cell death. However, this information needs to be brought together to provide an overview of how these compounds can be used as therapeutic tools for drug development and as a successful adjuvant strategy against sp.
Topics: Humans; Terpenes; Antiprotozoal Agents; Leishmania; Leishmaniasis; Cell Death; Biological Products
PubMed: 37799331
DOI: 10.3389/fcimb.2023.1260448 -
International Journal For Parasitology.... Dec 2021The Free-Living Amoeba species, Naegleria fowleri is the causative agent of a lethal encephalitis known as Primary Amoebic Encephalitis (PAM). Moreover, most of the...
The Free-Living Amoeba species, Naegleria fowleri is the causative agent of a lethal encephalitis known as Primary Amoebic Encephalitis (PAM). Moreover, most of the reported cases are often related to swimming and/or diving in aquatic environments. In addition, the current therapeutic options against PAM are not fully effective and hence, there is an urgent need to develop novel therapeutic agents against this disease. Previously isobenzofuranones compounds have been reported to present antiprotozoal and antifungal activity among others. However, to the best of our knowledge, these molecules have not been previously tested against N. fowleri. Therefore, the aim of this study was to evaluate the activity of 14 novel isobenzofuranones against this pathogenic amoeba. The most active and less toxic molecules, were assayed in order to check induction of Programmed Cell Death (PCD) in the treated amoebae. The obtained results showed that these molecules were able to eliminate N. fowleri trophozoites and also induced PCD. Therefore, the tested isobenzofuranones could be potential therapeutic candidates for the treatment of PAM.
Topics: Amebiasis; Amoeba; Animals; Antiprotozoal Agents; Naegleria fowleri; Trophozoites
PubMed: 34627024
DOI: 10.1016/j.ijpddr.2021.09.004 -
Molecules (Basel, Switzerland) Nov 2018The cytotoxic and antiprotozoal activities of the phytoquinoide, jacaranone, and related compounds have been an ongoing topic in recent drug discovery. Starting from the...
The cytotoxic and antiprotozoal activities of the phytoquinoide, jacaranone, and related compounds have been an ongoing topic in recent drug discovery. Starting from the natural product-derived cyclohexadienone scaffold, a series of nitrogen-containing derivatives were synthesized and subsequently evaluated for their antiproliferative and antiprotozoal activity. Anticancer potency was analyzed using different types of cancer cell lines: MDA-MB-231 breast cancer, CCRF-CEM leukemia, HCT-116 colon cancer, U251 glioblastoma, and, in addition, non-tumorigenic MRC-5 lung fibroblasts. Antiproliferative activities at micromolar concentrations could be shown. Antiprotozoal activity was assessed against NF54 and STIB900. For all compounds, selectivity indices (SI) were calculated based on assessed cytotoxicity towards L6 cells. In addition, the structure-activity-relationships and physicochemical parameters of these compounds are discussed.
Topics: Antineoplastic Agents; Antiprotozoal Agents; Biological Products; Cell Line; Cell Survival; Cyclohexenes; Humans; Molecular Structure; Parasitic Sensitivity Tests; Phytochemicals; Structure-Activity Relationship
PubMed: 30405045
DOI: 10.3390/molecules23112902 -
Drug Design, Development and Therapy 2017causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged... (Review)
Review
causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis.
Topics: Animals; Antiprotozoal Agents; Drug Design; Humans; Toxoplasma; Toxoplasmosis
PubMed: 28182168
DOI: 10.2147/DDDT.S60973