Antitrypanosomal Activity Research Articles

Filamentous Fungi-Derived Orsellinic Acid-Sesquiterpene Meroterpenoids: Fungal Sources, Chemical Structures, Bioactivities, and Biosynthesis.

Fungi-derived polyketide-terpenoid hybrids are important meroterpenoid natural products that possess diverse structure scaffolds with a broad spectrum of bioactivities. Herein, we focus on an ever-increasing group of meroterpenoids, orsellinic acid-sesquiterpene hybrids comprised of biosynthetic start unit orsellinic acid coupling to a farnesyl group or/and its modified cyclic products. The review entails the search of China National Knowledge Infrastructure (CNKI), Web of Science, Science Direct, Google Scholar, and PubMed databases up to June 2022. The key terms include "orsellinic acid", "sesquiterpene", "ascochlorin", "ascofuranone", and "Ascochyta viciae", which are combined with the structures of "ascochlorin" and "ascofuranone" drawn by the Reaxys and Scifinder databases. In our search, these orsellinic acid-sesquiterpene hybrids are mainly produced by filamentous fungi. Ascochlorin was the first compound reported in 1968 and isolated from filamentous fungus Ascochyta viciae (synonym: Acremonium egyptiacum; Acremonium sclerotigenum); to date, 71 molecules are discovered from various filamentous fungi inhabiting in a variety of ecological niches. As typical representatives of the hybrid molecules, the biosynthetic pathway of ascofuranone and ascochlorin are discussed. The group of meroterpenoid hybrids exhibits a broad arrange of bioactivities, as highlighted by targeting hDHODH (human dihydroorotate dehydrogenase) inhibition, antitrypanosomal, and antimicrobial activities. This review summarizes the findings related to the structures, fungal sources, bioactivities, and their biosynthesis from 1968 to June 2022.

In vitro and in vivo Antitrypanosomal Activities of Annona muricata Leaf Extracts in Trypanosoma brucei brucei Experimentally Infected Albino Rats

Aims: Trypanosomiasis is an important protozoan disease that affects domestic and wild animals as well as man. It is caused by the tsetse fly-transmitted extracellular hemo-flagellates that belong to the genus, Trypanosoma. In East and Southern Africa, Human African Trypanosomiasis (HAT) is caused by Trypanosoma brucei rhodesiense while in West and Central Africa, it is caused by T. b. gambiense. Animal trypanosomiasis on the other hand is caused by T. b. brucei, T. vivax, and T. congolense. In sub-Saharan Africa, about sixty million people are at risk of infection. This current study evaluates the antitrypanosomal efficacy of extracts of Annona muricata leaf in Trypanosoma brucei brucei infected albino rats.
 Place and Duration of Study: Animal Parasitology and Microbiology Research Unit, Department of Animal Production and Health, Federal University of Technology, Akure, Nigeria, between February and June, 2021.
 Methodology: In vitro antitrypanosomal analysis was done in varied concentrations of 2.5mg/ml, 5mg/ml and 10mg/ml using various solvent extracts (ethanolic, ethyl acetate, n-hexane, chloroform and aqueous). Diminazine aceturate and normal saline were used as positive and negative controls respectively. The In vivo assay was carried out through intraperitoneal administration of graded doses (200, 400 and 600mg/kg) of ethyl acetate and chloroform extracts of the plant for three consecutive days.
 Results: The n-hexane, chloroform and ethyl acetate extracts yielded high percentage DPPH free radical scavenging activity of 85.52, 80.00 and 78.49% respectively. Decrease in motility of the parasites at different times were observed in all extracts tested invitro. These responses were positively concentration-dependent. 10mg/ml concentration of chloroform and ethyl acetate showed complete cessation of parasite motility at 35 and 45 minutes respectively. These two extracts (ethyl acetate and chloroform extracts) which showed the best invitro responses, were subjected to invivo analysis. Both extracts caused decrease in trypanosome parasitemia and prolongation of mean survival days of the rats to 14.67days as compared with 6.83days in the negative control group. The extracts displayed dose-dependent significant (p ≤ 0.05) antitrypanosomal activities when compared with the negative and positive controls.
 Conclusion: The chloroform and ethyl acetate extracts of Annona muricata showed a relatively higher antitrypanosomal activity over other solvent extracts used in this study. Further fractionation, purification and isolation should be done to confirm the active components in this plant that is responsible for the antitrypanosomal activities recorded.

Type I-like metalloproteinase in the venom of the West African saw-scaled carpet viper (Echis ocellatus) has anti-trypanosomal activity against African trypanosomes

African trypanosomiasis is an infectious disease caused by hemoparasites of the genus Trypanosoma and remains a major health problem in Africa - killing around 4000 people and animals worth an estimated $5 billion, annually. The absence of a vaccine and satisfactory drug against African trypanosomiasis (AT) necessitates the continued search for new chemotherapy options. Owing to the rich biochemical diversity in snake venom, it has recently become a source of therapeutic peptides that are being explored for the development of novel drug candidates for diverse ailments such as cancers and infectious diseases. To explore this, Echis ocellatus venom (EOV) was investigated for the presence of an anti-Trypanosoma factor, with the subsequent aim to isolate and identify it. Crude EOV was collected and tested in vitro on the bloodstream form (BSF) i.e. long and slender morphological form of Trypanosoma brucei and T. congolense. This initial testing was followed by a sequential anti-trypanosomal assay guided purification of EOV using ethanol precipitation, distillation, and ion exchange (IEX) chromatography to obtain the active trypanocidal component. The purified anti-Trypanosoma factor, estimated to be a 52-kDa protein on SDS-PAGE, was subjected to in-gel trypsin digestion and 2D RP HPLC-MS/MS to identify the protein. The anti-Trypanosoma factor was revealed to be a zinc-dependent metalloproteinase that contains the HEXXHXXGXXH adamalysin motif. This protein may provide a conceptual framework for the possible design of a safe and effective anti-trypanosomal peptide for the treatment of AT.

Evaluation of the Antiparasitic and Antifungal Activities of Synthetic Piperlongumine-Type Cinnamide Derivatives: Booster Effect by Halogen Substituents.

A series of synthetic N-acylpyrrolidone and -piperidone derivatives of the natural alkaloid piperlongumine were prepared and tested for their activities against Leishmania major and Toxoplasma gondii parasites. Replacement of one of the aryl meta-methoxy groups by halogens such as chlorine, bromine and iodine led to distinctly increased antiparasitic activities. For instance, the new bromo- and iodo-substituted compounds 3 b/c and 4 b/c showed strong activity against L. major promastigotes (IC50 =4.5-5.8 μM). Their activities against L. major amastigotes were moderate. In addition, the new compounds 3 b, 3 c, and 4 a-c exhibited high activity against T. gondii parasites (IC50 =2.0-3.5 μM) with considerable selectivities when taking their effects on non-malignant Vero cells into account. Notable antitrypanosomal activity against Trypanosoma brucei was also found for 4 b. Antifungal activity against Madurella mycetomatis was observed for compound 4 c at higher doses. Quantitative structure-activity relationship (QSAR) studies were carried out, and docking calculations of test compounds bound to tubulin revealed binding differences between the 2-pyrrolidone and 2-piperidone derivatives. Microtubules-destabilizing effects were observed for 4 b in T. b. brucei cells.

In vitro and in vivo evaluation of efficacy of berberine chloride: Phyto-alternative approach against Trypanosoma evansi infection

Current chemotherapy against the Surra organism, Trypanosoma evansi has several limitations in terms of efficacy, toxicity, availability and emerging resistance. These reasons make the search of new chemo-preventive and chemo-therapeutic agent with high potency and low toxicity. Alkaloid phyto-molecules, berberine has shown promising anti-kinetoplastid activity against T. cruzi, T. congolense, T. brucei, Leishmania donovani and L. tropica. However, till date, there is no investigation of therapeutic efficacy of berberine chloride (BC) against T. evansi. The IC50 value of BC for growth inhibition of T. evansi at 24 h of culture was calculated as 12.15 µM. The specific selectivity index (SSI) of BC was calculated as 19.01 and 10.43 against Vero cell line and Equine PBMC’s, respectively. Thirteen drug target genes affecting various metabolic pathways were studied to investigate the mode of trypanocidal action of BC. In transcript analysis, the mRNA expression of arginine kinase 1 remained refractory to exposure with BC, which provides metabolic plasticity in adverse environmental conditions. In contrary, rest all the drug target gene were down-regulated, which indicates that drug severely affect DNA replication, cell proliferation, energy homeostasis, redox homeostasis and calcium homeostasis of T. evansi, leading to the death of parasite in low concentrations. It is the first attempt to investigate in vitro anti-trypanosomal activity of BC against T. evansi. These data imply that phytochemicals as alternative strategies can be explored in the future as an alternative treatment for Surra in animal.

Phytochemical Screening, GC-MS Analysis, and Evaluating In Vivo Antitrypanosomal Effects of a Methanolic Extract of Garcinia kola Nuts on Rats.

Trypanosomiasis is a serious disease that affects both humans and animals, causing social and economic losses. Efforts to find new therapeutic approaches are warranted to improve treatment options. Therefore, the purpose of this communication includes the phytochemical screening of a methanolic extract of Garcinia kola nuts and the in vivo evaluation of its biological activity against rats infected with Trypanosoma brucei brucei and treated with 4 different concentrations of the extract (0.01, 0.1, 1, and 10 mg/kg). Treatment with suramin served as a positive control, while the negative control received no drug. Since the general toxicity of the extract could be ruled out, efficacy was evaluated based on physiological changes, such as induction of trypanosome parasitemia, influence on body temperature, and body weight. Survival was assessed during this study. Physical parameters, behavioral characteristics, and various hematological indices were also monitored. Based on the (patho)physiological and behavioral parameters (e.g., no parasitemia, no increase in body temperature, an increase in body weight, no loss of condition, no alopecia, and no gangrene), the efficacy of the extract was evident, which was also confirmed by 100% survival, while in the negative control, all rats died during the observation period. Since overall very similar results were obtained as a result of treatment with the established suramin, the in vivo antitrypanosomal activity of a methanolic extract of G. kola nuts on rats can be demonstrated in this communication. This opens the way, for example, for further development of drug formulations based on this methanolic extract.

Isolation of Hennaminal and Isolation and Total Synthesis of Hennamide, Pyrrolinone Compounds from the Marine Cyanobacterium Rivularia sp.

Two new natural products were isolated from the marine cyanobacterium Rivularia sp. collected in Japan. Hennaminal possesses a very rare functional group, β,β-diamino unsaturated ketone, which has only been found in bohemamine-type natural products so far. Hennamide possesses a reactive N-acyl pyrrolinone moiety, which induces self-dimerization. The isolation and structure determination supported by computational chemistry and total synthesis, as well as the antitrypanosomal activities of hennaminal and hennamide are described.

Steroid and Triterpenoid Compounds with Antiparasitic Properties.

Parasitic diseases affect millions of people and animals, predominantly in the tropics, including visitors to tropical countries and other areas. Efficient and low-cost treatments for infections caused by various parasites are not yet available. Antiparasitic drugs have some drawbacks, such as toxicity and the development of resistance by parasites. This has motivated many researchers to focus on the discovery of safe, effective and affordable antiparasitic drugs, both among drugs already available for other diseases and new compounds synthesized or isolated from natural sources. Furthermore, steroid and triterpenoid compounds attract the attention of pharmacologists, chemists and biochemists owing to their broad application in the treatment of various diseases. Isolation of steroid and triterpenoid compounds from natural sources with antiparasitic efficacy is an attractive choice for scientists. On the other hand, these compounds can be transformed into more potent forms by modifying the basic skeleton. This review presents a collection of isolated and synthesized steroid and triterpenoid compounds from 2018 to 2021 that have been reported to be effective against certain parasitic protozoa and helminths. A total of 258 compounds have been identified with antimalarial, antitrypanosomal, antileishmanial, anti-Toxoplasma, and/or anthelmintic activity. The described investigations of antiparasitic compounds may be helpful for further drug development.

Total Synthesis and Structure Activity Relationship of Cynaropicrin

Cynaropicrin (1) is a sesquiterpene lactone natural product isolated from artichokes (Cynara scolymus). 1 has attractive biological activity including anti-trypanosomal activity, inhibition of NF-κB activation, antihepatitis C activity, etc. Herein, we report the first total synthesis of cynaropicrin 1. The structure activity relationship study is also described.

Exploring Synthetic Dihydrobenzofuran and Benzofuran Neolignans as Antiprotozoal Agents against Trypanosoma cruzi

Chagas disease is a neglected tropical disease that affects more than 8 million people. Although there are therapies against this disease, the search for new drugs is important because the current treatments show limited effectiveness and high toxicity. In this work, eighteen dihydrobenzofuran-type neolignans (DBNs) and two benzofuran-type neolignans (BNs) were synthesized and evaluated against amastigote forms of two Trypanosoma cruzi strains. The in vitro cytotoxicity and hemolytic activity of the most active compounds were also evaluated and their relationships with T. cruzi tubulin DBNs were investigated by an in silico approach. Four DBNs demonstrated activity against the T. cruzi Tulahuen lac-Z strain (IC50 from 7.96 to 21.12 µM), and DBN 1 exhibited the highest activity against the amastigote forms of the T. cruzi Y strain (IC50 3.26 μM). Compounds 1-4 showed CC50 values higher than antitrypanosomal activities, except for DBN 3. All DBNs with antitrypanosomal activity demonstrated CH50 higher than 100 µM. The in silico results indicated that DBNs 1, 2, and 4 are capable of destabilizing the dynamics of the tubulin-microtubule from the vinca site. These compounds displayed promising in vitro activity against T. cruzi, especially compound 1, and can be considered molecular prototypes for the development of new antiparasitic drugs.

Effect of partial O-methylation in dehydrodieugenol on its antitrypanosomal activity - correlation with the toxicity using cell membrane models

Biseugenol (1), a neolignan with antiprotozoal activity against Trypanosoma cruzi, was partially methylated, and the compound obtained – methyl biseugenol (2) – had its activity evaluated against the extracellular (trypomastigotes) and intracellular (amastigotes) forms of T. cruzi. It was observed that both compounds 1 and 2 exhibited similar effects against trypomastigotes (IC50 of 11.7 and 16.2 μM, respectively), whereas compound 2 displayed higher activity against amastigotes (IC50 = 8.2 μM) in comparison with biseugenol (IC50 = 15.4 μM). Additionally, reduced toxicity against NCTC cells for compound 2 was observed (CC50 > 200 μM), differently from compound 1 with CC50 = 58.0 μM. Aiming to understand better the molecular mechanism of the biological action of compound 2, the prodrug was incorporated into cellular membrane models constituted of Langmuir monolayers of the lipids dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylserine (DPPS), and dipalmitoylphosphatidylglycerol (DPPG). The lipid-drug interaction was inferred through tensiometry, surface potential, infrared spectroscopy (PM-IRRAS), and Brewster angle microscopy (BAM). The prodrug expanded DPPC and DPPG monolayers and condensed DPPE ones, as well as presented characteristic behaviors regarding the chemical structure of the lipid considering expansion-compression curves, surface potential-area isotherms, and stability of previously compressed monolayers to relevant-biological surface pressures. PM-IRRAS indicated a molecular disorder for DPPC and DPPS alkyl chains in the presence of the drug. BAM revealed the presence of domains in the DPPG and DPPE monolayers, which was probably induced by the prodrug. These data suggest, in general, that the lipid composition modulates the interaction of compound 2, whose results are expected to correlate to its trypanocidal activity, which involves the plasma membrane of T. cruzi as the primary target, i.e., the first barrier that the compound should encounter to interact with the microorganism.

STRYCHNOS SPINOSA LAM: COMPREHENSIVE REVIEW ON ITS MEDICINAL AND NUTRITIONAL USES.

Background: Most of the people living in developing countries rely on local remedies from traditional medicines to take care of their healthcare needs. In recent years, the use of medicinal plants increased considerably. Consequently, studies on medicinal plants are necessary to produce more effective drugs with fewer side-effects. This work aims to compile the dispersal data on Strychnos spinosa Lam., a medicinal plant with great therapeutic potential in traditional medicine, on its ethnobotanical uses, chemical compounds, as well as its pharmacological and nutritional effects. Material and Methods: To achieve the aforementioned aim, electronic databases such as Pubmed, Science Direct, Google scholar, Scopus and SciFinder were scanned. Results: Literature survey revealed that S. spinosa is used in the treatment of microbial infections, malaria, trypanosomiasis, intestinal worms, tuberculosis, infertility, gastrointestinal disorders, snake bite, hypertension, and diabetes mellitus among other ailments. The plant is also used as food material. S. spinosa contains many chemical compounds, such as alkaloids, terpenes, sterols, fatty acids, flavonoids, saponin, and others. The fruits are a source of important nutrients such as carbohydrates, sugars, proteins, vitamins and fibres. Experimental studies have shown numerous pharmacological properties, including antimicrobial, antiplasmodial, anti-trypanosomal, anti-leishmanial, anti-nematicidal, anti-inflammatory, anti-oxidant, antidiabetic and other activities. Conclusion: This review article provides comprehensive information on S. spinosa and its various extracts. Due to the promising effects of the plant extracts on various diseases and its nutritional values, there is a need for toxicity studies and clinical trials to assess the effects of its identified bioactive compounds.

Bioactive Clerodane Diterpenoids from the Leaves of Casearia coriacea Vent.

Casearia coriacea Vent., an endemic plant from the Mascarene Islands, was investigated following its antiplasmodial potentialities highlighted during a previous screening. Three clerodane diterpene compounds were isolated and identified as being responsible for the antiplasmodial activity of the leaves of the plant: caseamembrin T (1), corybulosin I (2), and isocaseamembrin E (3), which exhibited half maximal inhibitory concentrations (IC50) of 0.25 to 0.51 µg/mL. These compounds were tested on two other parasites, Leishmania mexicana mexicana and Trypanosoma brucei brucei, to identify possible selectivity in one of them. Although these products possess both antileishmanial and antitrypanosomal properties, they displayed selectivity for the malaria parasite, with a selectivity index between 6 and 12 regarding antitrypanosomal activity and between 25 and 100 regarding antileishmanial activity. These compounds were tested on three cell lines, breast cancer cells MDA-MB-231, pulmonary adenocarcinoma cells A549, and pancreatic carcinoma cells PANC-1, to evaluate their selectivity towards Plasmodium. This has not enabled us to establish selectivity for Plasmodium, but has revealed the promising activity of compounds 1-3 (IC50 < 2 µg/mL), particularly against pancreatic carcinoma cells (IC50 < 1 µg/mL). The toxicity of the main compound, caseamembrin T (1), was then evaluated on zebrafish embryos to extend our cytotoxicity study to normal, non-cancerous cells. This highlighted the non-negligible toxicity of caseamembrin T (1).

Molecular and phylogenetic analysis of a type K1 strain Trypanosoma evansi isolate from Nigerian cattle: An evaluation of the therapeutic effects of compounds from Brassica oleracea on the histopathology of infected wister rats

BackgroundUnderstanding the pathogenesis of animal trypanosomiasis can be improved by studying the genetics of bovine trypanosomes. Pathogenic animal trypanosomes are a major impediment to livestock production, with negative economic consequences spreading beyond Sub-Saharan Africa to subtropical regions of Northern Africa, Southeast Asia, and Central and South America. An atypical K1 strain of Trypanosoma evansi (T. evansi) isolates from infected cattle in Nigeria was analyzed. The therapeutic effect of phenolic-rich compounds on the histopathology of wistar rats infected with the K1 strain was studied. MethodsThe K1 strain T. evansi was analyzed molecularly using PCR and sequence analysis of the Spacer-1 ribosomal RNA gene. To assess the evolutionary relationship, this was phylogenetically compared to other species studied in different parts of the world. Thirty adult male wistar rats were divided into six groups of five each. Animals in group A served as the standard control (not infected). Group B animals were infected but not treated. Group C animals were infected and given 3.5 mg/kg body weight of the standard drug diminazene aceturate. Animals in groups D, E, and F were infected and treated with phenolic-rich compounds isolated from Brassica oleracea (B. oleracea) at concentrations of 100, 200, and 400 mg/kg body weight, respectively. The phytochemicals were extracted using standard analytical procedures, and GCMS analysis revealed the presence of phenolic-rich compounds. The animals were given 0.2 mg/ml trypanosome intraperitoneally, diluted with normal saline. The vital organs of the animals were harvested and histologically examined. ResultsThe nested PCR amplification of the trypanosome's ITS-1 region revealed a DNA amplicon of 627 base pairs. The rRNA nucleotide sequence was deposited in GenBank under the accession number MN462960. Basic Local Alignment search of the obtained ITS-1 rRNA sequences revealed that the K1 strain trypanosome and other strains from different regions have an evolutionary relationship. The phenolic-rich compounds had protective effects on the organs of infected animals, resulting in a decrease in parasitemia levels. They have anti-trypanosome activities at the minimum and maximum effective doses of 200 and 400 mg/kg body weight, respectively. ConclusionsThe K1 strain T. evansi was isolated from naturally infected cattle in this study. The results indicate that phenolic-rich compounds have anti trypanosoma activities capable of healing organ damage caused by trypanosomiasis.

A structure-based virtual high-throughput screening, molecular docking, molecular dynamics and MM/PBSA study identified novel putative drug-like dual inhibitors of trypanosomal cruzain and rhodesain cysteine proteases.

Virtual screening a collection of ~ 25,000 ChemBridge molecule collection identified two nitrogenous heterocyclic molecules, 12 and 15, with potential dual inhibitory properties against trypanosomal cruzain and rhodesain cysteine proteases. Similarity search in DrugBank found the two virtual hits with novel chemical structures with unreported anti-trypanosomal activities. Investigations into the binding mechanism by molecular dynamics simulations for 100ns revealed the molecules were able to occupy the binding sites and stabilise the protease complexes. Binding affinities calculated using the MM/PBSA method for the last 20ns showed that the virtual hits have comparable binding affinities to other known inhibitors from literature suggesting both molecules as promising scaffolds with dual cruzain and rhodesain inhibition properties, i.e. 12 has predicted ΔGbind values of -38.1 and -38.2kcal/mol to cruzain and rhodesain, respectively, and 15 has predicted ΔGbind values of -34.4 and -25.8kcal/mol to rhodesain. Per residue binding free energy decomposition studies and visual inspection at 100ns snapshots revealed hydrogen bonding and non-polar attractions with important amino acid residues that contributed to the ΔGbind values. The interactions are similar to those previously reported in the literature. The overall ADMET predictions for the two molecules were favourable for drug development with acceptable pharmacokinetic profiles and adequate oral bioavailability.

Antiparasitic Activities of Compounds Isolated from Aspergillus fumigatus Strain Discovered in Northcentral Nigeria.

In this study, we explored a fungal strain UIAU-3F identified as Aspergillus fumigatus isolated from soil samples collected from the River Oyun in Kwara State, Nigeria. In order to explore its chemical diversity, the fungal strain UIAU-3F was cultured in three different fermentation media, which resulted in different chemical profiles, evidenced by LC-ESI-MS-based metabolomics and multivariate analysis. The methanolic extract afforded two known compounds, fumitremorgin C (1) and pseurotin D (2). The in vitro antiparasitic assays of 1 against Trypanosoma cruzi and Plasmodium falciparum showed moderate activity with IC50 values of 9.6 µM and 2.3 µM, respectively, while 2 displayed IC50 values &gt; 50 µM. Molecular docking analysis was performed on major protein targets to better understand the potential mechanism of the antitrypanosomal and antiplasmodial activities of the two known compounds.

Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei

Trypanosoma brucei is a protozoan parasite that causes Human African Trypanosomiasis (HAT), a neglected tropical disease (NTD) that is endemic in 36 countries in sub-Saharan Africa. Only a handful drugs are available for treatment, and these have limitations, including toxicity and drug resistance. Using the natural product, curcumin, as a starting point, several curcuminoids and related analogs were evaluated against bloodstream forms of T. b. brucei. A particular subset of dibenzylideneacetone (DBA) compounds exhibited potent in vitro antitrypanosomal activity with sub-micromolar EC50 values. A structure–activity relationship study including 26 DBA analogs was initiated, and several compounds exhibited EC50 values as low as 200 nM. Cytotoxicity counter screens in HEK293 cells identified several compounds having selectivity indices above 10. These data suggest that DBAs offer starting points for a new small molecule therapy of HAT.

PHYTOCHEMICAL AND PHARMACOLOGICAL ASPECTS OF THE ALKALOIDS OF MALVACEAE sensu lato SPECIES: A REVIEW

Malvaceae sensu lato is a family containing about 245 genera and 4,465 species mainly distributed across tropical and subtropical regions worldwide. Species of this family usually contain alkaloids with anti-inflammatory, antinociceptive, antiparasitic, antimicrobial and anticancer properties due to its secondary metabolites. In this context, this review aims to checklist the alkaloids isolated from Malvaceae sensu lato species, evaluating their chemical profile and pharmacological potential, providing a broad and concise overview of these secondary metabolites. The results were collected from scientific databases such as Web of Science, Scifinder, Pubmed, ScienceDirect and Google Scholar, using the keywords “Alkaloids” and “Malvaceae”. Several pharmacological/ biological activities are reported in literature for the most varied alkaloid nuclei, such as: vasorelaxation of the mesentery of rats (cryptolepinone), antitrypanosomal activity (waltherione) and anti-inflammatory and bronchodilator activity (vasicine), which highlights a succession of activities related to this class of secondary metabolites. Presented data report the importance of the Malvaceae sensu lato family, demonstrating the biological relevance of its alkaloids, in order to contribute to scientific knowledge and the development of new drugs.

Synthesis of 5-aryl/heterylidene substituted 2-imino-4-thiazolidinones possessing 1,3,4-thiadiazole moiety and their antitrypanosomal activity

A novel 1,3,4-thiadiazole containing 2-iminothiazolidine-4-ones 4a-b were synthesized through the reaction of 2-chloro-N-(5-ethyl/allylsulfanyl-[1,3,4]thiadiazol-2-yl)-acetamides 1a-b with ammonium thiocyanate in dry acetone. Condensation of 4a-b with various carbonyl compounds according to the standard Knoevenagel procedure yielded the corresponding 5-arylidene- (5a-d), 5-heterylidene- (6a-c), 5-isatinylidene- (7a-b) and 5-(3-phenyl-2-propene-1-ylidene)- (8a-b) derivatives. All the newly synthesized compounds were confirmed by their elemental analysis and spectral data. Synthesized compounds 4a, 5a, 5b, 6a, 6c and 7a were screened for their in vitro antitrypanosomal activity against T. brucei gambience (Feo strain). The 5-ylidene substituted compounds with S-allyl group in position 5 of thiadiazole cycle (5a, 5b, 6a and 7a) displayed good to excellent antitrypanosomal potency with a range IC50 = 7.3-12.8 µM.

Rutin‐Rich Flavonoid Subfraction of Annona senegalensis Mitigates Trypanosoma brucei brucei Infection and Hematobiochemical Changes in Infected Mice

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 &lt; 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.