Antimicrobial and antiparasitic activities of three algae from the northwest coast of Algeria

The objective of this study was to investigate the biological activities of Algerian algae, Sargassum vulgare, Cladostephus hirsutus and Rissoella verruculosa. Antimicrobial activity of the crude extracts and their fractions was assessed using the disc diffusion assay, the minimum inhibitory concentration and the minimum bactericidal concentration. Antiparasitic activity was studied in vitro against the blood stream forms of Trypanosoma brucei brucei and the intraerythrocytic stages of Plasmodium falciparum. Ethyl acetate (EA) fractions of the three tested algae showed more potent antimicrobial activity against S. aureus (7–14.5 mm) and B. cereus (7–10.75 mm), MIC values ranged from 0.9375 to 7.5 mg mL^?1 and MBC values > 15 mg mL^?1. Concerning the antiparasitic activity, EA factions of S. vulgare (IC₅₀ = 9.3 μg mL^?1) and R. verruculosa (IC₅₀ = 11.0 μg mL^?1) were found to be more effective against T. brucei brucei, whereas the three EA fractions were little active against P. falciparum.     

Synthesis,characterization and in vitro antiprotozoal studies of iron(III) complexes of some antimalarial drugs

We present the synthesis, characterization and in vitro antiplasmodial and antitrypanosomal studies of iron(III) complexes of amodiaquine, trimethoprim and pyrimethamine. The complexes have been characterized by elemental analyses, electronic and IR spectroscopy and room temperature magnetic susceptibility measurements. The spectra are consistent with octahedral geometry around the metal ions. The complexes were tested for in vitro activity against cultures of Plasmodium falciparum, Tripanosoma brucei rhodosiense, L. donovani and Tripanosoma cruzi. One of the complexes showed enhanced activity of about 8.4 times more than chloroquine against the resistant strain of Plasmodium falciparum.     

Anti-infective assessment of Senecio smithioides (Asteraceae) and isolation of 9-oxoeuryopsin,a furanoeremophilane-type sesquiterpene with antiplasmodial activity

The search for anti-infective activity in the antipyretic plant Senecio smithioides was conducted. Petroleum ether (PE), dichloromethane (CH₂Cl₂), ethyl acetate (EtOAc) and hydroethanolic (96% EtOH) extracts, and compounds 9-oxoeuryopsin (1), epoxydecompostin (2) and senecionine (3) were obtained from the aerial parts. All extracts and 1 were tested against chloroquine-resistant strain of Plasmodium falciparum (ref. chloroquine), Trypanosoma cruzi (ref. nifurtimox), Leishmania braziliensis, Leishmania amazonensis and Leishmania donovani (ref. pentamidine), Staphylococcus aureus and Escherichia coli (ref. gentamicin) and, Neurospora crassa and Candida albicans (ref. ketoconazole). The PE extract exhibited the strongest in vitro activity against Plasmodium falciparum IC₅₀ < 1.0 μg/mL. 1 was established as a potent antiplasmodial compound with an IC₅₀ = 1.2 μg/mL, 5.2 μM. Other antiparasitic activities were recorded for all extracts and 1. Antibacterial and antifungal activity was negligible.     

Isolation and Structural Elucidation of Compounds from Pleiocarpa bicarpellata and Their In Vitro Antiprotozoal Activity

Species of the genus Pleiocarpa are used in traditional medicine against fever and malaria. The present study focuses on the isolation and identification of bioactive compounds from P. bicarpellata extracts, and the evaluation of their antiprotozoal activity. Fractionation and isolation combined to LC-HRMS/MS-based dereplication provided 16 compounds: seven indole alkaloids, four indoline alkaloids, two secoiridoid glycosides, two iridoid glycosides, and one phenolic glucoside. One of the quaternary indole alkaloids (7) and one indoline alkaloid (15) have never been reported before. Their structures were elucidated by analysis of spectroscopic data, including 1D and 2D NMR experiments, UV, IR, and HRESIMS data. The absolute configurations were determined by comparison of the experimental and calculated ECD data. The extracts and isolated compounds were evaluated for their antiprotozoal activity towards Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum, as well as for their cytotoxicity against rat skeletal myoblast L6 cells. The dichloromethane/methanol (1:1) root extract showed strong activity against P. falciparum (IC₅₀ value of 3.5 µg/mL). Among the compounds isolated, tubotaiwine (13) displayed the most significant antiplasmodial activity with an IC₅₀ value of 8.5 µM and a selectivity index of 23.4. Therefore, P. bicarpallata extract can be considered as a source of indole alkaloids with antiplasmodial activity.     

2-(Nitroaryl)-5-Substituted-1,3,4-Thiadiazole Derivatives with Antiprotozoal Activities: In Vitro and In Vivo Study

Nitro-containing compounds are a well-known class of anti-infective agents, especially in the field of anti-parasitic drug discovery. HAT or sleeping sickness is a neglected tropical disease caused by a protozoan parasite, Trypanosoma brucei. Following the approval of fexinidazole as the first oral treatment for both stages of T. b. gambiense HAT, there is an increased interest in developing new nitro-containing compounds against parasitic diseases. In our previous projects, we synthesized several megazole derivatives that presented high activity against Leishmania major promastigotes. Here, we screened and evaluated their trypanocidal activity. Most of the compounds showed submicromolar IC₅₀ against the BSF form of T. b. rhodesiense (STIB 900). To the best of our knowledge, compound 18c is one of the most potent nitro-containing agents reported against HAT in vitro. Compound 18g revealed an acceptable cure rate in the acute mouse model of HAT, accompanied with noteworthy in vitro activity against T. brucei, T. cruzi, and L. donovani. Taken together, these results suggest that these compounds are promising candidates to evaluate their pharmacokinetic and biological profiles in the future.     

Design, synthesis and biological evaluation of new oxazines with potential antiparasitic activity

A series of new oxazines with potential antiparasitic activity was prepared using Diels-Alder reactions, based on terpenes derived from eucarvone as dienes and nitrosoarenes with different electronic characteristics as dienophiles. The biological activity was evaluated with in vitro assays against Plasmodium falciparum, Trypanosoma cruzi and Trypanosoma brucei rhodesiense. Some of these oxazines have activities in the 20-50 μM range, and may be leaders for the development of novel antiparasitic drugs with improved pharmacological properties.     

Antimicrobial compounds from root,stem bark and seeds of Melia volkensii

Three compounds, toosendanin (1), kulactone (2) and scopoletin (3), were isolated from either the root bark and/or the stem bark of Melia volkensii. Their structures were determined on the basis of spectroscopic data generated and by comparison with data from the literature. 1 and 2, isolated for the first time from M. volkensii, exhibited significant (p < 0.05) activity against Escherichia coli with minimum inhibitory concentration of 12.5 μg/mL, close to that of neomycin (6.25 μg/mL). The compounds also exhibited high activity against Aspergillus niger (MIC 6.25 μg/mL compared to 2.5 μg/mL for clotrimazole). Dichloromethane and methanol seed, hexane stem bark and methanol root bark extracts exhibited activities towards Escherichia coli, Staphylococcus aureus, Aspergillus niger and Plasmodium falciparum, respectively. Antimicrobial activity of the plant towards A. niger, P. falciparum and S. aureus is reported for the first time in the current work.     

Development of Novel Isoindolone-Based Compounds against Trypanosoma brucei rhodesiense

This study identified the isoindolone ring as a scaffold for novel agents against Trypanosoma brucei rhodesiense and explored the structure-activity relationships of various aromatic ring substitutions. The compounds were evaluated in an integrated in vitro screen. Eight compounds exhibited selective activity against T. b. rhodesiense (IC₅₀<2.2 μm ) with no detectable side activity against T. cruzi and Leishmania infantum. Compound 20 showed low nanomolar potency against T. b. rhodesiense (IC₅₀=40 nm ) and no toxicity against MRC-5 and PMM cell lines and may be regarded as a new lead template for agents against T. b. rhodesiense. The isoindolone-based compounds have the potential to progress into lead optimization in view of their highly selective in vitro potency, absence of cytotoxicity and acceptable metabolic stability. However, the solubility of the compounds represents a limiting factor that should be addressed to improve the physicochemical properties that are required to proceed further in the development of in vivo-active derivatives.     

New fac-tricarbonyl rhenium(I) semicarbazone complexes: synthesis,characterization, and biological evaluation

Expanding our previous work on salicylaldehyde semicarbazone metal complexes as prospective anti-trypanosomal agents, five new fac-Re^I(CO)₃-containing complexes with ligands of this semicarbazone series were synthesized and characterized. An atypical coordination mode of these potentially tridentate ligands through only the carbonylic oxygen and the azomethine nitrogen (the so-called N,O fashion) was demonstrated by IR spectroscopy and supported by theoretical calculations. Three of the compounds showed moderate in vitro anti-Trypanosoma cruzi activity and increased activity with respect to the corresponding free ligands. The brominated ligands, 5-bromo-2-hydroxybenzaldehyde semicarbazone (L2) and 5-bromo-2-hydroxy-3-methoxybenzaldehyde semicarbazone (L5), led to the most active rhenium(I) complexes. These compounds are among the few reported examples of rhenium complexes bearing in vitro activity against T. cruzi.     

In vitro cytotoxicity of some Narcissus plants extracts

This study compares the chloroform extracts of bulbs and roots of Narcissus papyraceus Ker Gawl. and Narcissus tazetta L. The cytotoxicity of the plant extracts was evaluated against human hepatocellular carcinoma cell line (HEPG2) and colon carcinoma cell line (HCT116) in comparison to doxorubicin. The extracts from the after-flowering (AF) bulbs of N. tazetta L. and N. papyraceus exhibited strong cytotoxic activity against HEPG2 (IC₅₀: 2.2, 3.5 μg mL^? 1) and HCT116 (IC₅₀: 4.2, 3.9 μg mL^? 1) cell lines, respectively. N. tazetta L. bulbs exhibited the least cell viability percentage in HepG-2 cell line (5.32%), while the AF root extracts of N. papyraceus exhibited the least cell viability percentage in HCT116 cell line (4.93%), when applied at a concentration of 50 μg mL^? 1, thereby being more active than doxorubicin at the same concentration.     

Synthesis and Anti-Trypanosoma cruzi Biological Evaluation of Novel 2-Nitropyrrole Derivatives

Human American trypanosomiasis, called Chagas disease, caused by T. cruzi protozoan infection, represents a major public health problem, with about 7000 annual deaths in Latin America. As part of the search for new and safe anti-Trypanosoma cruzi derivatives involving nitroheterocycles, we report herein the synthesis of ten 1-substituted 2-nitropyrrole compounds and their biological evaluation. After an optimization phase, a convergent synthesis methodology was used to obtain these new final compounds in two steps from the 2-nitropyrrole starting product. All the designed derivatives follow Lipinski’s rule of five. The cytotoxicity evaluation on CHO cells showed no significant cytotoxicity, except for compound 3 (CC₅₀ = 24.3 µM). Compound 18 appeared to show activity against T. cruzi intracellular amastigotes form (EC₅₀ = 3.6 ± 1.8 µM) and good selectivity over the vero host cells. Unfortunately, this compound 18 showed an insufficient maximum effect compared to the reference drug (nifurtimox). Whether longer duration treatments may eliminate all parasites remains to be explored.     

Synthesis and biological evaluation of 2-substituted vinylgembisphosphonates against Plasmodium falciparum and Trypanosoma brucei

Abstract

A series of 2-substituted vinylidene-1,1-bisphosphonate esters and their acids were synthesized and tested in vitro for activity against Plasmodium falciparum and Trypanosoma brucei. For each compound, % parasite viability in treated wells was calculated relative to untreated controls for both P. falciparum and T. brucei. Fifty percentage inhibitory concentration (IC₅₀) was also determined for the compounds. Chloroquine and pentamidine were used as positive control drug standards for activity against P. falciparum and T. brucei, respectively. The esters had better antiparasitic activity compared to their corresponding acids. Some of the compounds reduced % parasite viability to as low as 24.3% for P. falciparum and down to 0.602% for T. brucei. Tetraethyl-2-(o-tolyl)-ethene-1,1-bisphosphonate (3b) recorded the best IC₅₀ against T. brucei which was 0.0345?µmol/mL.     

Antiprotozoal Activity and Cytotoxicity of Novel 1,7‐Dioxadispiro[5.1.5.2]pentadeca‐9,12‐dien‐11‐one Derivatives from Amomum aculeatum

Cytotoxicity against the KB cancer cell line as a lead bioactivity‐guided fractionation of the petroleum ether extract of rhizomes of Amomum aculeatum Roxb. led to the isolation of three novel dioxadispiro[5.1.5.2]pentadeca‐9,12‐dien‐11‐one derivatives. The structures of aculeatin A ( 1 ), aculeatin B ( 2 ), and aculeatin C ( 3 ) were established as rel‐(2R,4R,6S)‐ and rel‐(2R,4R,6R)‐4‐hydroxy‐2‐tridecyl‐1,7‐dioxadispiro[5.1.5.2]pentadeca‐9,12‐dien‐11‐one ( 1 and 2 , resp.) and rel‐(2R,4R,6R)‐2‐[4‐(3‐dodecyl‐2‐heptyl‐3‐hydroxy‐6‐oxocylohexa‐1,4‐dienyl)‐2‐oxobutyl]‐4‐hydroxy‐1,7‐dioxadispiro[5.1.5.2]pentadeca‐9,12‐dien‐11‐one ( 3 ) by extensive spectroscopic analyses, particularly ¹³C‐NMR, inverse‐gated ¹³C, HMQC, HMBC, NOESY, and INADEQUATE NMR experiments as well as mass spectrometry. The aculeatins represent a novel type of natural products. All compounds showed high cytotoxicity against the KB cell line: 1 , IC₅₀=1.7 μM ; 2 , IC₅₀=2.0 μM ; 3 , IC₅₀=1.6 μM . Additional testing against two Plasmodium falciparum strains as well as against trypomastigote forms of Trypanosoma brucei rhodesiense and Trypanosoma cruzi showed strong activities, particularly against P. falciparum strain K1 ( 1 , IC₅₀=0.18 μM ; 2 , IC₅₀=0.43 μM ; 3 , IC₅₀=0.37 μM ).     

Easy-To-Access Quinolone Derivatives Exhibiting Antibacterial and Anti-Parasitic Activities

The cell wall of Mycobacterium tuberculosis (Mtb) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, Mtb resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (Plasmodium falciparum and Trypanosoma brucei brucei) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-Mtb activity with MIC₉₀ values in the range of 0.24–31 µM. Cross-screening against P. falciparum and T.b. brucei, identified several compounds with antiprotozoal activities in the range of 0.4–20 µM. Compounds were generally inactive against ESKAPE pathogens, with only compounds 8c, 8g and 13 exhibiting moderate to poor activity against S. aureus and A. baumannii.     

A Comparative Study of Anti-Candida Activity and Phenolic Contents of the Calluses from Lythrum salicaria L. in Different Treatments

In the study, anti-Candida activity and phenol contents of Lythrum salicaria L. calli and wild species have been evaluated. The seeds of L. salicaria (Lythraceae), collected from Lahidjan City in the north of Iran, were cultured in Murashige and Skoog medium (MSM) with a supplement, gibberellin, to germinate. Callus inductions were performed from segments of seedling on MSM containing different concentrations of plant growth regulators, 2,4-dichlorophenoxyacetic acid (2,4-D) and 6-benzylaminopurine (BAP). The activity of calluses extracts, wild plant, gallic acid, and 3,3′,4′-tri-O-methylellagic acid-4-O-β-d-glucopyranoside (TMEG) as the main phenolic compounds against Candida albicans was assessed using cup plate diffusion method. The total phenols contents of calli and wild plant extracts were analyzed using Folin–Ciocalteu reagent. The callus formation in MSM supplemented with various concentrations of 2,4-D and BAP were 0–100 %. Anti-Candida activity of callus extract which obtained from MSM supplemented with 2,4-D and BAP (1 mg?dm^?3) was similar to the wild plant extract. Minimum inhibitory concentration values of gallic acid and TMEG were obtained as 0.312 and 2.5 mg?cm^?3, respectively. Gallic acid equivalent values in all treatments were from 0 to 288 μg GAE mg^?1. Phenolic contents of plant aerial parts (331?±?3.7 μg GAE mg^?1) and the callus, which developed in MSM including 1 mg?dm^?3 of both 2,4-D and BAP, showed the same phenolic value and exhibited anti-Candida extract activity.     

Synthesis,characterization and antiprotozoal studies of some metal complexes of antimalarial drugs

Metal complexes of the antimalarials trimethoprim (TMP), chloroquine (CQ), and pyrimethamine (pyrm) formulated as [Mn(TMP)Cl₂(CH₃OH)], [Co(TMP)₂Cl₂(CH₃OH)], [Pt(CQ)₂Cl₂] and [Cu(pyrm)₂(CH₃COO)₂] have been synthesized and characterized by elemental analysis, magnetic susceptibility measurements, IR and UV-Vis spectroscopy. The IR and electronic spectra are consistent with the proposed geometry for the complexes. The Mn(II) and Pt(II) complexes are four coordinate while the Cu(II) and Co(II) have octahedral geometry. The complexes were tested for in vitro activity against cultures of Trypanosoma cruzi, L. donovani, T. b. rhodesiense and the resistant strains of Plasmodium falciparum to determine their antiprotozoal activities and for their cytotoxicity with L-6 cells. The Pt(II) complex of chloroquine showed enhanced activity against the resistant strain of Plasmodium falciparum.     

Design,Synthesis and Antiparasitic Evaluation of Click Phospholipids

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure–activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC₅₀) against THP-1 macrophages ranged between 50 and 100 μM. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases.     

Antileishmanial Activities of Medicinal Herbs and Phytochemicals In Vitro and In Vivo: An Update for the Years 2015 to 2021

Leishmaniasis is one of the most neglected tropical diseases that present areal public health problems worldwide. Chemotherapy has several limitations such as toxic side effects, high costs, frequent relapses, the development of resistance, and the requirement for long-term treatment. Effective vaccines or drugs to prevent or cure the disease are not available yet. Therefore, it is important to dissect antileishmanial molecules that present selective efficacy and tolerable safety. Several studies revealed the antileishmanial activity of medicinal plants. Several organic extracts/essential oils and isolated natural compounds have been tested for their antileishmanial activities. Therefore, the aim of this review is to update and summarize the investigations that have been undertaken on the antileishmanial activity of medicinal plants and natural compounds derived, rom plants from January 2015 to December 2021. In this review, 94 plant species distributed in 39 families have been identified with antileishmanial activities. The leaves were the most commonly used plant part (49.5%) followed by stem bark, root, and whole plant (21.9%, 6.6%, and 5.4%, respectively). Other plant parts contributed less (<5%). The activity was reported against amastigotes and/or promastigotes of different species (L. infantum, L. tropica, L. major, L. amazonensis, L. aethiopica, L. donovani, L. braziliensis, L. panamensis, L. guyanensis, and L. mexicana). Most studies (84.2%) were carried out in vitro, and the others (15.8%) were performed in vivo. The IC₅₀ values of 103 plant extracts determined in vitro were in a range of 0.88 µg/mL (polar fraction of dichloromethane extract of Boswellia serrata) to 98 µg/mL (petroleum ether extract of Murraya koenigii). Among the 15 plant extracts studied in vivo, the hydroalcoholic leaf extract of Solanum havanense reduced parasites by 93.6% in cutaneous leishmaniasis. Voacamine extracted from Tabernaemontana divaricata reduced hepatic parasitism by ≈30 times and splenic parasitism by ≈15 times in visceral leishmaniasis. Regarding cytotoxicity, 32.4% of the tested plant extracts against various Leishmania species have a selectivity index higher than 10. For isolated compounds, 49 natural compounds have been reported with anti-Leishmania activities against amastigotes and/or promastigotes of different species (L. infantum, L. major, L. amazonensis, L. donovani and L. braziliensis). The IC₅₀ values were in a range of 0.2 µg/mL (colchicoside against promastigotes of L. major) to 42.4 µg/mL (dehydrodieuginol against promastigotes of L. amazonensis). In conclusion, there are numerous medicinal plants and natural compounds with strong effects (IC₅₀ < 100 µg/mL) against different Leishmania species under in vitro and in vivo conditions with good selectivity indices (SI > 10). These plants and compounds may be promising sources for the development of new drugs against leishmaniasis and should be investigated in randomized clinical trials.     

Antiviral properties from plants of the Mediterranean flora

Natural products are a successful source in drug discovery, playing a significant role in maintaining human health. We investigated the in vitro cytotoxicity and antiviral activity of extracts from 18 traditionally used Mediterranean plants. Noteworthy antiviral activity was found in the extract obtained from the branches of Daphne gnidium L. against human immunodeficiency virus type-1 (EC₅₀ = 0.08 μg/mL) and coxsackievirus B5 (EC₅₀ = 0.10 μg/mL). Other relevant activities were found against BVDV, YFV, Sb-1, RSV and HSV-1. Interestingly, extracts from Artemisia arborescens L. and Rubus ulmifolius Schott, as well as those from D. gnidium L., showed activities against two different viruses. This extensive antiviral screening allowed us to identify attractive activities, offering opportunities to develop lead compounds with a great pharmaceutical potential.     

In vitro antiprotozoal activity of extracts of five Turkish Lamiaceae species

The in vitro antiprotozoal activities of crude methanolic extracts from the aerial parts of five Lamiaceae plants (Salvia tomentosa, S. sclarea, S. dichroantha, Nepeta nuda subsp. nuda and Marrubium astracanicum subsp. macrodon) were evaluated against four parasitic protozoa, i.e. Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani and Plasmodium falciparum. The cytotoxic potentials of the extracts on L6 cells were also evaluated. Melarsoprol, benznidazole, miltefosine, chloroquine and podophyllotoxin were used as reference drugs. All crude MeOH extracts showed antiprotozoal potential against at least three parasites, so they were dispersed in water and partitioned against n-hexane and chloroform to yield three subextracts that were screened in the same test systems. The n-hexane extract of N. nuda was the most active against T. brucei rhodesiense while the CHCl3 extracts of S. tomentosa and S. dichroantha showed significant activity against L. donovani. All organic extracts displayed in vitro antimalarial and moderate trypanocidal activities against T. cruzi with the n-hexane extract of S. sclarea being the most active against the latter. The extracts displayed low or no cytotoxicity towards mammalian L6 cells.