N-Pyrazolyl- and N-Triazolylamines and -Ureas as Antileishmanial and Antitrypanosomal Drugs.

Three types of modifications of antileishmanial pyrazole lead compounds 7 and 8 were conducted to expand understanding of the relationships between structural features and antileishmanial/antitrypanosomal activity: (1) the pyrazole core was retained or replaced by a 1,2,4-triazole ring; (2) various aryl moieties including 2-fluorophenyl, pyridin-3-yl and pyrazin-2-yl rings were attached at 3-position of the core azole; (3) either arylmethylamino or ureido substituents were introduced at 5-position of the azole core. The synthesis followed established routes starting with esters 9 or 15 and anhydride 21. The synthesized 3-arylpyrazoles and 3-aryl-1,2,4-triazoles had only very low antileishmanial activity. The 2-fluorophenyl-substituted pyrazole 18c revealed the highest antileishmanial activity of this series of compounds, but its IC50 value (20 µM) still indicates low activity. However, low micromolar antitrypanosomal activity was detected for the pyridin-3-yl-substituted pyrazoles 12b (IC50=4.7 µM) and 14a (IC50=2.1 µM). Their IC50 values are comparable with the IC50 values of the reference compounds benznidazole and nifurtimox. Whereas only low unspecific cytotoxicity at the primary peritoneal mouse macrophages (PMM) was detected, considerable cytotoxicity at MRC-5 human fibroblast cells was found for both pyrazoles 12b an 14a. The activity of pyrazole 12b against T. cruzi is 4-fold higher than its unspecific MRC-5 cytotoxicity.

Spiro-Acridine Compound as a Pteridine Reductase 1 Inhibitor: in silico Target Fishing and in†vitro Studies.

Among the many neglected tropical diseases, leishmaniasis ranks second in mortality rate and prevalence. In a previous study, acridine derivatives were synthesized and tested for their antileishmanial activity against L. chagasi. The most active compound identified in that study (1) showed a single digit IC50 value against the parasite (1.10 µg/mL), but its macromolecular target remained unknown. Aiming to overcome this limitation, this work exploited inverse virtual screening to identify compound 1's putative molecular mechanism of action. In vitro assays confirmed that compound 1 binds to Leishmania chagasi pteridine reductase 1 (LcPTR1), with moderate affinity (Kd=33,1 µM), according to differential scanning fluorimetry assay. Molecular dynamics simulations confirm the stability of LcPTR1-compound 1 complex, supporting a competitive mechanism of action. Therefore, the workflow presented in this work successfully identified PTR1 as a macromolecular target for compound 1, allowing the designing of novel potent antileishmanial compounds.

Late-Stage Diversification of Pyrazoles as Antileishmanial Agents.

N-Pyrazolylcarboxamides and N-pyrazolylureas represent promising lead compounds for the development of novel antileishmanial drugs. Herein, we report the late-stage diversification of 3-bromopyrazoles 10 A/B and 14 A by Pd-catalyzed Sonogashira and Suzuki-Miyaura cross coupling reactions. The electron-withdrawing properties of the cyano moiety in 4-position of the pyrazole ring limited the acylation of the primary amino moiety in 5-position. A large set of pyrazoles bearing diverse aryl and alkynyl substituents in 3-position was prepared and the antileishmanial and antitrypanosomal activity was recorded. The urea 38 lacking the electron withdrawing cyano moiety in 4-position and containing the large 4-benzylpiperidinoo moiety exhibited a modest antileishmanial (IC50=19 µM) and antitrypanosomal activity (IC50=7.9 µM)). However, its considerable toxicity against the PMM and MRC-5 cells indicates low selectivity, i. e. a small gap between the desired antiparasitic activity and undesired cytotoxicity of <2- to 4-fold.

Amphotericin B loaded nanoemulsion: Optimization, characterization and in-vitro activity against L. donovani promastigotes.

The present work aimed to develop and evaluate AmB-loaded nano-emulsion (AmB-NE) which will augment the solubility of AmB and lead to enhanced anti-leishmanial activity. The composition of AmB-NE was optimized by systematic screening followed by DoE-extreme vertices mixture design. The optimized NE revealed mean droplet size and PDI of 44.19 ± 5.5 nm, 0.265 ± 0.0723, respectively. The NE could efficiently encapsulate AmB with drug content and efficiency 83.509 ± 0.369% and 81.659 ± 0.013%, respectively. The presence of cholesterol and stearyl amine retarded the release (P < 0.0001) of AmB significantly compared to AmB suspension. The AmB-NE and pure AmB suspension demonstrated the IC50 of 0.06309 µg/mL and 0.3309 µg/mL against L.donovani promastigotes after 48 h incubation. The formulation was robust at all exaggerated stability conditions such as freeze-thaw and centrifugation. These findings indicate that AmB-NE is an attractive approach to treat visceral leishmaniasis with improved activity.

HPLC method for quantifying verbascoside in Stizophyllum perforatum and assessment of verbascoside acute toxicity and antileishmanial activity.

We report the chemical composition of the crude leaf extracts obtained from Stizophyllum perforatum (Cham.) Miers (Bignoniaceae), a simple high-performance liquid chromatography-diode array detection (HPLC-DAD) method based on mangiferin as an internal standard to quantify verbascoside, and the verbascoside acute oral toxicity and antileishmanial activity. HPLC-high-resolution mass spectrometry-DAD (HPLC-HRMS-DAD) analyses of the crude ethanol S. perforatum leaf extracts (CE-1 and CE-2) revealed that verbascoside was the major constituent in both extracts. CE-1 was purified, and verbascoside and casticin, among other compounds, were isolated. The developed HPLC-DAD method was validated and met the required standards. Investigation of the CE-2 acute toxicity indicated a lethal dose (LD50) greater than 2,000 mg/kg of body weight. Both CE-1 and CE-2 exhibited antileishmanial activity. The isolated compounds, verbascoside and casticin, also displayed antileishmanial activity with effective concentrations (IC50) of 6.23 and 24.20 µM against promastigote forms and 3.71 and 18.97 µM against amastigote forms of Leishmania amazonensis, respectively, but they were not cytotoxic to J774A.1 macrophages. Scanning electron microscopy of the L. amazonensis promastigotes showed that the parasites became more rounded and that their plasma membrane was altered in the presence of verbascoside. Additionally, transmission electron microscopy demonstrated that vacuoles emerged, lipids accumulated, kinetoplast size increased, and interstitial extravasation occurred in L. amazonensis promastigotes exposed to verbascoside. These findings suggest that S. perforatum is a promising candidate for further in vivo investigations against L. amazonensis.

Synergistic antileishmanial activity of erythrodiol, uvaol, and oleanolic acid isolated from olive leaves of cv. Chemlali.

This study aimed to assess the antileishmanial activity of biomolecules obtained from Olea europaea L. leaves and twigs recovered from eight Tunisian cultivars. The extraction was first carried out with 80% methanol, and then the obtained extract was fractionated using three solvents of increasing polarity: cyclohexane (CHX), dichloromethane (DCM) and ethyl acetate (EtOAc). The antileishmanial activity was determined against leishmanial strains responsible for cutaneous, visceral, and mucocutaneous leishmaniasis. The cyclohexane fraction of the leaves of cv. Chemlali from the region of Sidi-Bouzid exhibited the strongest leishmanicidal activity against all the tested leishmanial strains. The inhibition concentrations (IC50) were 16.5, 14.5, and 7.4 µg mL-1 for Leishmania mexicana (cutaneous), Leishmania braziliensis (mucocutaneous), and Leishmania donovani (visceral), respectively. Interestingly, low cytotoxicity was observed on THP-1 cells with selective indexes (SI) ranging from 22.8 to 50.5. HPLC-HRMS and full-house NMR analysis allowed the identification of three triterpenic compounds, oleanolic acid (IC50 = 64.1 µg mL-1), erythrodiol (IC50 = 52.0 µg mL-1), and uvaol (IC50 = 53.8 µg mL-1). Antileishmanial activity of uvaol and oleanolic acid has been previously reported. However, this work constitutes the first report of the antileishmanial activity of erythrodiol which showed combinatorial interaction with uvaol (IC50 = 26.1 µg mL-1) against Leishmania tropica. The mixture of the three compounds, as major ones, exhibited an enhanced activity against Leishmania tropica (IC50 = 16.3 µg mL-1) compared to erythrodiol alone or the combination of uvaol and erythrodiol. This finding is of great importance and needs further investigation. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03825-3.

In Vitro and In Silico Evaluations of the Antileishmanial Activities of New Benzimidazole-Triazole Derivatives.

Benzimidazole and triazole rings are important pharmacophores, known to exhibit various pharmacological activities in drug discovery. In this study, it was purposed to synthesize new benzimidazole-triazole derivatives and evaluate their antileishmanial activities. The targeted compounds (5a-5h) were obtained after five chemical reaction steps. The structures of the compounds were confirmed by spectral data. The possible in vitro antileishmanial activities of the synthesized compounds were evaluated against the Leishmania tropica strain. Further, molecular docking and dynamics were performed to identify the probable mechanism of activity of the test compounds. The findings revealed that compounds 5a, 5d, 5e, 5f, and 5h inhibited the growth of Leishmania tropica to various extents and had significant anti-leishmanial activities, even if some orders were higher than the reference drug Amphotericin B. On the other hand, compounds 5b, 5c, and 5g were found to be ineffective. Additionally, the results of in silico studies have presented the existence of some interactions between the compounds and the active site of sterol 14-alpha-demethylase, a biosynthetic enzyme that plays a critical role in the growth of the parasite. Therefore, it can be suggested that if the results obtained from this study are confirmed with in vivo findings, it may be possible to obtain some new anti-leishmanial drug candidates.

Design, synthesis, and biological evaluation of quinoline-piperazine/pyrrolidine derivatives as possible antileishmanial agents.

In pursuance of our efforts to expand the scope of novel antileishmanial entities, a series of thirty-five quinoline-piperazine/pyrrolidine, and other heterocyclic amine derivatives were synthesized via a molecular hybridization approach and examined against intracellular amastigotes of luciferase-expressing Leishmania donovani. The preliminary in vitro screening suggests that twelve compounds in the series exhibited better inhibition against amastigote form with good IC50 values ranging from 2.09 to 8.89 µM and lesser cytotoxicity in contrast to the standard drug miltefosine (IC50 9.25 ± 0.17 µM). Based on the satisfactory selectivity index (SI), two compounds were tested for in vivo leishmanicidal efficacy against Leishmania donovani/golden hamster model. Compounds 33 and 46 have shown significant inhibition of 56.32%, and 49.29%, respectively, in vivo screening at a daily dose of 50 mg/kg for 5 days. The pharmacokinetic results confirmed that 33 and 46 have satisfactory IP exposure with adequate parameters. Collectively, Compound 33 was identified as the most significant potential lead that could be employed as a prototype for future optimizations.

Antiplasmodial and Antileishmanial Activities of a New Limonoid and Other Constituents from the Stem Bark of Khaya senegalensis.

Plasmodium falciparum and Leishmania 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 (KS-MeOH) of the stem bark of the Cameroonian medicinal plant Khaya senegalensis and its isolated compounds. The purification of KS-MeOH led to the isolation of a new ordered limonoid derivative, 21ß-hydroxybourjotinolone A (1a), together with 15 known compounds (1bc-14) using a repeated column chromatography. Compound 1a was obtained in an epimeric mixture of 21α-melianodiol (1b) and 21ß-melianodiol (1c). 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 Plasmodium falciparum and the promastigote form of Leishmania donovani (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 P. falciparum, amphotericin B for L. donovani, and podophyllotoxin for cytotoxicity against RAW 264.7 cells. The extract and fractions exhibited moderate to potent antileishmanial activity with 50% inhibitory concentrations (IC50) ranging from 5.99 ± 0.77 to 2.68 ± 0.42 µg/mL, while compounds displayed IC50 values ranging from 81.73 ± 0.12 to 6.43 ± 0.06 µg/mL. They were weakly active against the chloroquine-sensitive/sulfadoxine-resistant Pf3D7 strain but highly potent toward the multidrug-resistant PfDd2 (extracts, IC50 2.50 ± 0.12 to 4.78 ± 0.36 µg/mL; compounds IC50 2.93 ± 0.02 to 50.97 ± 0.37 µg/mL) with selectivity indices greater than 10 (SIDd2 > 10) for the extract and fractions and most of the derived compounds. Of note, the limonoid mixture [21ß-hydroxylbourjotinolone A (1a) + 21α-melianodiol (1b) + 21ß-melianodiol (1c)] exhibited moderate activity against P. falciparum and L. donovani. 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.

Phytochemical, antileishmanial, antifungal and cytotoxic profiles of Thymelaea tartonraira (L.) All. extracts.

Extracts from leaves and stems of Thymelaea tartonraira (L.) All. growing in Tunisia were characterised for the presence of flavonoids and phenolic acids by LC-ESI-MS analysis. Twelve flavonoids and ten phenolic acids were detected for the first time in the aerial parts of this plant species, the most abundant compounds being gallic acid, kaempferol, catechin, chlorogenic acid, naringenin and acacetin. The extracts were subjected to in vitro antileishmanial, antifungal and cytotoxic assays, showing promising antileishmanial activity for the E6 dichloromethane extract from the stems (IC50 values of 1.12 ± 0.50 and 5.41 ± 1.84 µg/mL on L. donovani axenic and intramacrophagic amastigotes, respectively) at the level of the reference drug miltefosine for axenic model. No antifungal activity was observed against Candida albicans (CAAL) and Aspergillus fumigatus (ASFU) strains, with the exception of the E6 dichloromethane extract (IC50 value of 25.28 ± 4.89 µg/mL on CAAL93 strain). Low toxicity was also highlighted against macrophages Raw 264.7 cells. These promising results point out Thymelaea tartonraira (L.) All. extracts as a valuable source of new natural products to combat leishmaniasis.

Biomedical Applications of Biosynthesized Nickel Oxide Nanoparticles.

Nickel oxide nanoparticles have gained tremendous attention recently in a variety of scientific domains thanks to their characteristic chemical, physical, optical, and biological properties. Due to the diversity of applications in various fields, different physicochemical methods have been used to synthesize nickel oxide nanoparticles. However, most conventional methods use hazardous chemicals during synthesis and become liable for potential health risks, while others are expensive and require a lot of energy to synthesize nanoparticles. As a result, the nanoparticles become less biocompatible and biologically inefficient. Biogenic synthesis of nanoparticles is currently proposed as a valuable alternative to the physical and chemical methods, as it is a simple, non-toxic, cheap, green and facile approach. This synthetic method uses biological substrates such as plant extracts, microorganisms, and other biological products to synthesize nickel oxide nanoparticles. The various phytochemicals from plant extracts, enzymes or proteins from microorganisms, and other biological derivatives play as reducing, stabilizing, and capping agents to provide bioactive and biocompatible nickel oxide nanoscale material. This review discusses current findings and trends in the biogenic synthesis of nickel oxide nanoparticles and their biological activities such as antibacterial, antifungal, antileishmanial, and anticancer, with an emphasis on antimicrobial and anticancer activity along with their mechanistic elucidation. Overall, this thorough study provides insight into the possibilities for the future development of green nickel oxide nanoparticles as therapeutic agents for a variety of ailments.

Design, synthesis and antitrypanosomatid activity of 2-nitroimidazole-3,5-disubstituted isoxazole compounds based on benznidazole.

Chagas disease and leishmaniasis are neglected diseases of high priority as a public health problem. Pharmacotherapy is based on the administration of a few drugs, which exhibit hazardous adverse effects and toxicity to the patients. Thus, the search for new antitrypanosomatid drugs is imperative to overcome the limitations of the treatments. In this work, 46 2-nitroimidazole 3,5-disubstituted isoxazole compounds were synthesized in good yields by [3 + 2] cycloaddition reaction between terminal acetylene (propargyl-2-nitroimidazole) and chloro-oximes. The compounds were non-toxic to LLC-MK2 cells. Compounds 30, 35, and 44 showed in vitro antichagasic activity, 15-fold, 12-fold, and 10-fold, respectively, more active than benznidazole (BZN). Compounds 30, 35, 44, 45, 53, and 61 acted as substrates for the TcNTR enzyme, indicating that this might be one of the mechanisms of action involved in their antiparasitic activity. Piperazine series and 4-monosubstituted compounds were potent against T. cruzi parasites. Besides the in vitro activity observed in compound 45, the in vivo assay showed that the compound only reduced the parasitemia levels by the seventh-day post-infection (77%, p > 0.001) compared to the control group. However, 45 significantly reduced the parasite load in cardiac tissue (p < 0.01) 11 days post-infection. Compounds 49, 52, and 54 showed antileishmanial activity against intracellular amastigotes of Leishmania (L.) amazonensis at the same range as amphotericin B. These findings highlight the antitrypanosomatid properties of 2-nitroimidazole 3,5-disubstituted isoxazole compounds and the possibility in using them as antitrypanosomatid agents in further studies.

Anti-Leishmania amazonensis Activity, Cytotoxic Features, and Chemical Profile of Allium sativum (Garlic) Essential Oil.

Human tegumentary leishmaniasis (HTL) is a serious tropical disease caused by Leishmania amazonensis. Developing new leishmanicidal agents can help overcome current treatment challenges, such as drug resistance and toxicity. Essential oils are a source of lipophilic substances with diverse therapeutic properties. This study aimed to determine the anti-L. amazonensis activity, cytotoxicity, and chemical profile of Allium sativum essential oil (ASEO). The effect of ASEO on parasite and mammalian cells viability was evaluated using resazurin and MTT assays, respectively. The oil's effect against intracellular amastigotes was also determined. Transmission electron microscopy was used to assess the ultrastructural changes induced by ASEO. In addition, the chemical constituents of ASEO were identified by gas chromatography-mass spectrometry (GC-MS). The cytotoxic potential was evaluated in vitro and in silico. The oil displayed IC50 of 1.76, 3.46, and 3.77 µg/mL against promastigotes, axenic, and intracellular amastigotes, respectively. Photomicrographs of treated parasites showed plasma membrane disruption, increased lipid bodies, and autophagic-like structures. ASEO chemical profiling revealed 1,2,4,6-tetrathiepane (24.84%) and diallyl disulfide (16.75%) as major components. Computational pharmacokinetics and toxicological analysis of ASEO's major components demonstrated good oral bioavailability and better toxicological endpoints than the reference drugs. Altogether, the results suggest that ASEO could be an alternative drug candidate against HTL.

In Vitro Anti-Leishmanial Activity of Glucosinolate Fraction from Alyssum linifolium Steph. ex Willd (Brassicaceae).

Objectives: The intracellular parasitic protozoan, Leishmania spp., causes several forms of diseases in humans. Cytotoxicity and emergence of new strains resistance to the current anti-leishmanial drugs have encouraged researchers to focus on new resources. Glucosinolates (GSL) are found mainly in the Brassicaceae family with potential cytotoxic and anti-parasitic properties. The present study reports in vitro antileishmanial activity of the GSL fraction from Alyssum linifolium seeds against Leishmania major. Materials and Methods: The GSL fraction was prepared by ion-exchange and reversed-phase chromatography. For the assessment of antileishmanial activity, the promastigotes and amastigotes of L. major were treated with different concentrations of the fraction (75-625 µg/mL). Results: The IC50 was 245 µg/mL for anti-promastigote effect of the GSL fraction and 250 µg/mL for its anti-amastigote effect that had a significant difference (p<0.05) with both glucantime and amphotericin B. The selectivity index of the GSL fraction (15.8), to glucantime and amphotericin B, was greater than 10, indicating the selective effect of this fraction against L. major amastigotes. Glucoiberverin was the major constituent of the GSL fraction characterized using nuclear magnetic resonance and electron ionization-mass spectrometry spectra. Based on gas chromatography-mass spectrometry data, iberverin and iberverin nitrile, the hydrolysis constituents from glucoiberverin, included 76.91% of the total seed volatiles. Conclusion: The results suggest that GSLs like glucoiberverin could be considered a new promising candidate for further studies on antileishmanial activity.

Antileishmanial and Antiplasmodial Activities of Secondary Metabolites from the Root of Antrocaryon klaineanum Pierre (Anacardiaceae).

Antrocaryon klaineanum is traditionally used for the treatment of back pain, malaria, female sterility, chlamydiae infections, liver diseases, wounds, and hemorrhoid. This work aimed at investigating the bioactive compounds with antileishmanial and antiplasmodial activities from A. klaineanum. An unreported glucocerebroside antroklaicerebroside (1) together with five known compounds (2-6) were isolated from the root barks of Antrocaryon klaineanum using chromatographic techniques. The NMR, MS, and IR spectroscopic data in association with previous literature were used for the characterization of all the isolated compounds. Compounds 1-4 are reported for the first time from A. klaineanum. The methanol crude extract (AK-MeOH), the n-hexane fraction (AK-Hex), the dichloromethane fraction (AK-DCM), the ethyl acetate fraction (AK-EtOAc), and compounds 1-6 were all evaluated for their antiparasitic effects against Plasmodium falciparum strains susceptible to chloroquine (3D7), resistant to chloroquine (Dd2), and promastigotes of Leishmania donovani (MHOM/SD/62/1S). The AK-Hex, AK-EtOAc, AK-MeOH, and compound 2 were strongly active against Dd2 strain with IC50 ranging from 2.78 ± 0.06 to 9.30 ± 0.29 µg/mL. Particularly, AK-MeOH was the most active-more than the reference drugs used-with an IC50 of 2.78 ± 0.06 µg/mL. The AK-EtOAc as well as all the tested compounds showed strong antileishmanial activities with IC50 ranging from 4.80 ± 0.13 to 9.14 ± 0.96 µg/mL.

In vitro and in vivo antileishmanial activity of the hanging sedge flavonoids based on bio- guided fractionation assay.

As a major public health issue, cutaneous leishmaniasis (CL) has a number of complications, including drug resistance and poor response to conventional treatments. Over the last decade, research on natural sources for finding new antileishmanial agents has been a critical part of tropical disease research. Natural products also should be regarded as one of the most valuable applications for CL infection drug development. In this study, we assessed the in vitro and in vivo antileishmanial potential of Carex pendula Huds. (hanging sedge) methanolic extract and its fractions against Leishmania major produced cutaneous infection. Although the methanolic extract and its fractions exhibited suitable activity, the ethyl acetate fraction showed the best activity (with the half maximal inhibitory concentration IC50  = 1.627 ± 0.211 mg/mL). The toxicity and selectivity indices (SI) of all samples were determined in murine peritoneal macrophage cells (J774A.1) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. The flavonoid components of the ethyl acetate fraction were identified using liquid chromatography electrospray ionization mass spectrometry (LC-ESI MS/MS). Nine chemical compounds were identified in this fraction, including three flavonols, four flavanonols, and two flavan derivatives. L. major-infected mice were used as an in vivo model because the methanolic extract was effective against L. major promastigotes in the mammalian cell line J774A.1 with SI = 2.514 (tail lesion size model). In silico analysis of identified compounds also revealed a favorable interaction between compounds 2-5 and L. major protein targets (3UIB, 4JZX, 4JZB, 5L4N, and 5L42). According to the findings of this study, the ethyl acetate fraction (as flavonoid fraction) exhibited considerable in vitro antileishmanial activity.

Thiazolidin-4-one-based derivatives - Efficient tools for designing antiprotozoal agents. A review of the last decade.

Thiazolidin-4-one derivatives have a wide range of therapeutic implementations and clinical significance for medicinal chemistry. This heterocyclic ring has been reported to possess a variety of biological activities, including antiprotozoal activities that have inspired scientists to integrate this scaffold with different pharmacophoric fragments to design novel and effective antiprotozoal compounds. There are reviews describing thiazolidin-4-ones small molecules as good candidates with a single type of antiprotozoal activity, but none of these show collected news associated with the antiprotozoal activity of thiazolidin-4-ones and their SAR analysis from the last decade. In this review we are focusing on the antitoxoplasmic, anti-trypanosomal, antimalarial, antileishmanial, and antiamoebic activity of these derivatives, we attempt to summarize and analyze the recent developments with regard to the antiprotozoal potential of 4-TZD covering the structure-activity relationship and main molecular targets. The importance of various structural modifications at C2, N3, and C5 of the thiazolidine-4-one core has also been discussed in this review. We hope that all information concluded in this review can be useful for other researchers in constructing new effective antiprotozoal agents.

Antileishmanial Activity of the Essential Oils from Three Trees Obtained in Different Phenological Stages.

PURPOSE: Leishmaniasis is a parasitic disease found in tropical areas, and it affects up to 12 million individuals globally. Chemotherapies now available include drawbacks such as toxicity, high cost, and parasite resistance. This work aimed to evaluate the antileishmanial properties of essential oils (EOs) extracted from aerial parts of Cupressus sempervirens (C. sempervirens), Tetraclinis articulata (T. articulata), and Pistacia lentiscus (P. lentiscus) trees. METHODS: The EOs were obtained by hydro-distillation, and chemical composition was determined by gas chromatography coupled to mass spectrometry at three phenological stages. The EOs were evaluated in vitro for antileishmanial activities against Leishmania major (L. major) and Leishmania infantum (L. infantum). The cytotoxicity effect was also tested against murine macrophagic cells (Raw264.7 lines). RESULTS: Results showed that P. lentiscus and T. articulata EOs presented low and moderate antileishmanial activity against L. infantum and L. major. However, C. sempervirens EO from the fructification stage gave an important selectivity index (23.89 and 18.96 against L. infantum and L. major, respectively). This activity was more interesting than those of amphotericin chemical drugs. Antileishmanial activity for this EO was highly correlated with germacrene D content (r = 1.00). This compound presented a SI equal to 13.34 and 10.38 for the two strains. According to the Principal Component Analysis (PCA), the distribution of the three phenological stages proved that the chemical composition of the EOs affected the antileishmanial activity. PCA revealed that SI was positively correlated with α-pinene, germacrene D and the sesquiterpene hydrocarbon class. Cupressus sempervirens EO can provide a source of germacrene D that can be used as a new alternative to chemical drugs for the treatment of antileishmanial diseases. CONCLUSION: C. sempervirens EO seemed to be a highly active antileishmanial agent and a natural alternative for chemical drugs to treat several leishmanial strains.

Antileishmanial Activity and In Silico Molecular Docking Studies of Malachra alceifolia Jacq. Fractions against Leishmania mexicana Amastigotes.

Malachra alceifolia Jacq. (family Malvaceae), known as "malva," is a medicinal plant used as a traditional therapy in many regions of America, Africa and Asia. Traditionally, this plant is used in the form of extracts, powder and paste by populations for treating fever, stomachache, inflammation, and parasites. However, the ethnopharmacological validation of M. alceifolia has been scarcely researched. This study showed that the chloroform fraction (MA-IC) and subfraction (MA-24F) of the leaves of M. alceifolia exhibited a potential antileishmanial activity against axenic amastigotes of Leishmania mexicana pifanoi (MHOM/VE/60/Ltrod) and had high and moderate cytotoxic effects on the viability and morphology of macrophages RAW 264.7. This study reports, for the first time, possible terpenoid metabolites and derivatives present in M. alceifolia with activity against some biosynthetic pathways in L. mexicana amastigotes. The compounds from the subfractions MA-24F were highly active and were analyzed by gas chromatography-mass spectrometry (GC-MS) and by a molecular docking study in L. mexicana target protein. This study demonstrates the potential modes of interaction and the theoretical affinity energy of the metabolites episwertenol, α-amyrin and methyl commate A, which are present in the active fraction MA-24F, at allosteric sites of the pyruvate kinase, glyceraldehyde-3-phosphate dehydrogenase, triose phosphate isomerase, aldolase, phosphoglucose isomerase, transketolase, arginase and cysteine peptidases A, target proteins in some vital biosynthetic pathways were responsible for the survival of L. mexicana. Some phytoconstituents of M. alceifolia can be used for the search for potential new drugs and molecular targets for treating leishmaniases and infectious diseases. Furthermore, contributions to research and the validation and conservation of traditional knowledge of medicinal plants are needed globally.

Development and Characterization of Pharmaceutical Systems Containing Rifampicin.

Rifampicin is a potent antimicrobial drug with some suboptimal properties, such as poor stability, low solubility, and variable bioavailability. Therefore, in the current study, a multicomponent complex between rifampicin, γ-cyclodextrin, and arginine was prepared with the aim of improving drug properties. Solubility was evaluated by phase-solubility studies. The mechanism of interaction was established through proton nuclear magnetic resonance spectroscopy and molecular modeling. Physicochemical characterization was investigated using Fourier transform-infrared spectroscopy, powder X-ray diffraction, and scanning electron microscopy. The dissolution properties, antimicrobial activity (antibacterial, antibiofilm, and antileishmanial), and stability of the different samples were studied. The results obtained in this investigation demonstrate that multicomponent complexes can improve the water solubility and dissolution rate of rifampicin, as well as its antibacterial and antileishmanial action, and present suitable stability. In conclusion, rifampicin complexed with γ-cyclodextrin and arginine is an attractive approach for developing pharmaceutical dosage forms of rifampicin with increased antimicrobial activities.