Search Results (88)

Given the known biological activity of both natural and synthetic substituted 1H-phenalen-1-ones, the generation of a small chemically and structurally diverse 1H-phenalen-1-one-based library of compounds was warranted. Herein, we have synthesized several groups of compounds to broaden and improve the chemical diversity of our 1H-phenalen-1-one collection. Additionally, we have also introduced hydroxyl, amides or carboxylic groups onto the core, or nitrogen atoms into the core, to increase the chemical diversity while also lowering the ClogP values to aid their water solubility. Notably, we have also improved the synthetic routes to several compounds of interest and have observed the unexpected formation of phenoxazine and acridin-7-one systems during cross-coupling reactions with polyfunctional anilines. Combining the compounds generated in this work with previous ones has enabled us to create a library of chemically diverse 1H-phenalen-1-one available for screening assays. Evaluation of anti-plasmodial activity against the chloroquine-resistant Plasmodium falciparum strain FCR3 revealed four compounds with notable activity, three of which exhibited IC₅₀ values below 1 µM, while none displayed significant cytotoxicity at 10 µM. Full article

The naphthoquinone skeleton is known for broad biological applications and, in particular, for antiparasitic efficacy. As part of our ongoing search for new antiprotozoal naphthoquinone derivatives, we incorporated computer-aided optimization models utilizing physicochemical parameters into our approach. Herein, we report on the synthesis of 21 new benzamido–menadione and naphthoquinone derivatives via the Kochi–Anderson reaction. The antiprotozoal activity of all the synthesized compounds was evaluated against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity towards L6 cells was also determined, and the respective selectivity indices (SI) were calculated. Several ligand efficiency metrics, such as LLE, SILE, and FQ, were calculated, and the results were visualized in scatterplots. Almost all of the synthesized benzamido–menadione derivatives exhibited high activity against NF54 (IC₅₀ < 1 µM), with the strongest activity and excellent selectivity observed in the 2-fluoro-5-trifluoromethylbenzamido derivative 2f (IC₅₀ = 0.021 µM, SI = 10,000). Specific ligand efficiency metrics, such as SILE, LLE or FQ, showed a clear correlation with the corresponding antiplasmodial activities. Toxicity predictions confirmed low acute oral toxicity for most compounds, further supporting their potential as safe drug candidates. Our findings highlight the benzamido–menadione scaffold as a viable option for new antiplasmodial drugs. Full article

The study of various microorganisms isolated from an Indian Ocean sponge, Scopalina hapalia ML-263, led to the selection of a promising Actinobacteria strain, Micromonospora sp. SH-82. Genomic analysis identified this strain as a new species, revealing the presence of 23 biosynthetic gene clusters (BGCs), some of which are associated with the synthesis of specialized metabolites such as polyketides deriving from polyketide synthases (PKSs). The strain was cultivated under favorable conditions for the production of bioactive molecules, resulting in the isolation and identification of seven microbial metabolites. Three of them are potentially novel, two erythronolides and one erythromycin, all characterized by a rare C10–C11 double bond. Some of these compounds also display atypical conformations, forming hemiacetals or spiroacetals. Their identification was achieved through detailed chemical analyses (NMR and ESI⁺-HRMS). A molecular networking approach was employed to assess the presence of potentially novel molecules in the microbial crude extract, supported by the identification of isolated molecules. Four molecules (1, 2, 3 and 5) were evaluated for their cytotoxic activities against cancer cell lines (HCT-116 and MDA-MB-231) and the immortalized retinal pigment epithelial RPE1 cells. No activity was observed in the latter, suggesting a lack of toxicity toward healthy cells. Moreover, megalomicin C1 (3), one of the isolated compounds, showed interesting antiplasmodial activity against Plasmodium falciparum 3D7, with an IC₅₀ of 6.37 ± 2.99 µM. Full article

Background: Among the alkaloids from Cassia siamea, cassiarin A has outstanding antiprotozoal activity, but structure–activity relationships for this chemotype were only poorly understood until now. Methods: We worked out efficient approaches to hitherto underexplored analogs (12 examples) on three synthesis routes which mainly comprised variations in the methyl groups at C-2 and C-5. The new compounds were tested for antiprotozoal and cytotoxic activities. Results: Introduction of a (substituted) benzene ring at C-2 led to a significant enhancement of activity against Plasmodium falciparum, while modifications of the methyl group at C-5 and the phenolic group had detrimental effects. Two of the 2-phenyl analogs further showed a resistance index comparable to the one of the reference drug chloroquine. Although the novel derivatives did not show hemolytic effects, investigation on human endothelial (HUVEC) cells at relevant concentrations indicated strong cytotoxic effects on human cells. Conclusions: Systematic structure modifications of cassiarin A led to a significant enhancement of antiplasmodial activity, but the observed strong cytotoxicity to human cells renders this library of cassiarin A derivatives inadequate for drug development. Full article

Peptaibols are linear fungal peptides featuring α,α-dialkylated amino acids (e.g., α-aminoisobutyric acid (Aib), isovaline (Iva)) and characteristic C-terminal alcohol groups. Despite their promising antibacterial and antiplasmodial activities, detailed biosynthetic studies remain limited. A genome-guided study of the fungus Trichodema sp. SK1-7, isolated from decaying wood, revealed the production of previously described trichorozin IV (1), along with novel SF4-type peptaibol 2 (trichorozin V). The structures of these compounds were elucidated through MS analysis, NMR study and advanced Marfey’s method. The genome of Trichoderma sp. SK1-7 harbors two PKS-NRPS hybrid gene clusters containing 14 and 18 adenylation domains. Analysis of the modular architecture suggested that trichorozins are synthesized by a 14-module protein via a module skipping mechanism. Genome mining revealed several types of short peptaibol synthase architectures (10–14 adenylation domains) across various Trichoderma species, accompanied by similar long peptaibol synthases. Furthermore, putative Aib/Iva biosynthesis machinery in Trichoderma was identified, showing specific architectures potentially involved in regulating peptaibol biosynthesis. Feeding experiments demonstrated that peptaibol production depends on the ratio of Iva/Aib. The isolated compounds exhibited moderate antibacterial and cytotoxic activities along with a synergistic effect when combined with membrane-targeting antibiotics. Our findings suggest that genome-guided approaches hold promise for further development of peptabiotics with a wide range of applications, including antibiotic adjuvants. Full article

Plasmodione is a potent early antiplasmodial compound. A metabolic study on mice treated with plasmodione revealed that 6-hydroxy–plasmodione was the main metabolite eliminated in the urine of treated mice. To block the metabolic pathway in the host, the introduction of fluorine at C-6 of the 3-benzylmenadione core was applied and showed potent antiplasmodial activity similar to that of the plasmodione analogue in vitro. In this work, a library of 38 6-fluoro-3-benzylmenadione analogues (a series) was constructed by incorporating structurally diverse groups in place of the 4-(trifluoromethyl) substituent present in the antiplasmodial plasmodione, via three synthetic routes. All new compounds were tested against the P. falciparum NF54 strain and for cytotoxicity with the rat L6 line. With a fluorine atom at C-6, A-a-21 was revealed to be the only compound from the a series, superior to the 6-H- analogue from the b series, with an IC₅₀ value of 70 nM versus 200 nM. Then, five other fluorine-based 3-benzylmenadiones, in which the fluorine was introduced in various positions of the 3-benzylmenadione core, were synthetized to assist our understanding of the impact of fluorine on antiplasmodial potencies in vitro; in particular, the aim here was to compare the effects of human serum and P. berghei species in these drug screens. This was also conducted in vivo with the P. berghei-infected mouse model. In the P. berghei species assay, PD and the 4′-fluoro-3′-trifluoromethyl-benzylmenadione A-b-9 exhibited a similar antiplasmodial behavior toward P. falciparum versus P. berghei. In the human serum versus Albumax assays, only the 6-fluoro–plasmodione showed a lower shift factor between Albumax assays and human serum conditions, suggesting a lower protein binding for the 6-F-PD compared to plasmodione or A-b-9. In vivo, 6-fluoro–plasmodione proved to be the most potent 3-benzylmenadione, reducing parasitemia by 50% after oral administration at 50 mg/kg. Full article

The serendipitous discovery of antiparasitic drugs, such as quinine and artemisinin, of plant origin reveals that searching new chemical pharmacophores from medicinal plants is valuable. The present study sought to explore the antiplasmodial, antileishmanial, and antitrypanosomal activities of Lippia adoensis extracts. Crude extracts of L. adoensis leaves and twigs, which were obtained by extraction using 70% ethanol in water, were assayed for antiplasmodial activity against P. falciparum 3D7 and Dd2 through the SYBR green I-based fluorescence assay; and for antileishmanial, antitrypanosomal, and cytotoxic effects on Leishmania donovani, Trypanosoma brucei brucei, and Vero cells, respectively, using resazurin colorimetric assays. In vitro phytochemical analysis of L. adoensis extracts was performed using standard methods. Moreover, liquid chromatography–mass spectrometry (LC-MS) feature-based detection and molecular networking flow on Global Natural Product Social (GNPS) were also used for the phytochemical screening of L. adoensis extracts. Crude extracts from L. adoensis inhibited the growth of P. falciparum (3D7 and Dd2) (IC₅₀s; (3D7): 10.00 and 97.46 μg/mL; (Dd2): 29.48 and 26.96 μg/mL), L. donovani (IC₅₀s: 22.87–10.52 μg/mL), and T. brucei brucei (IC₅₀s: 2.30–55.06 μg/mL). The extracts were found to be non-cytotoxic to Vero cells, thus yielding median cytotoxic concentrations (CC₅₀s) above 100 μg/mL. In vitro phytochemical analysis of the crude extracts revealed the presence of alkaloids, terpenoids, phenolic compounds, and carbohydrates. The LC-MS tandem molecular networking flow predicted that the extracts contained valsafungin A and bacillamidin in the first cluster, and fatty acids, ketone, and aldehyde derivatives in the second cluster. Overall, the present study demonstrated the antiparasitic effects of L. adoensis extracts, thus justifying the use of this plant in the traditional treatment of fever and malaria conditions. Nevertheless, detailed metabolomic studies and antiparasitic mechanisms of action of the extracts are expected to unveil the potential antiparasitic hit compounds. Full article

Malaria remains a major global health problem that has been exacerbated by the impact of the COVID-19 pandemic on health systems. To combat this, the World Health Organization (WHO) has set a target of driving forward research into innovative treatment methods such as new drugs and vaccines. Quinones, particularly 1,4-naphthoquinones, have been identified as promising candidates for the development of antiprotozoal drugs. Herein, we report several methods for the preparation of 2-benzyl-1,4-naphthoquinones. In particular, the silver-catalyzed Kochi–Anderson radical decarboxylation is well suited for the preparation of these compounds. The antiprotozoal activity of all synthesized compounds was evaluated against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity towards L6 cells was also determined, and the respective selectivity indices (SI) were calculated. The synthesized compounds exhibited good antiplasmodial activity against the P. falciparum (NF54) strain, particularly (2-fluoro-5-trifluoromethylbenzyl)-menadione 2e, which showed strong efficacy and high selectivity (IC₅₀ = 0.006 µM, SI = 7495). In addition, these compounds also displayed favorable physicochemical properties, suggesting that the benzylnaphthoquinone scaffold may be a viable option for new antiplasmodial drugs. Full article

Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute major global health problems, especially in developing countries; however, the development of drug resistance coupled with the toxicity of current treatments has hindered their management. The involvement of certain enzymes (dihydrofolate reductase [DHFR]) or proteins (potassium channels) in the pathogenesis of these protozoan diseases is undeniable. In this study, a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y, and Z) and one K⁺ channel blocker (E4031) were screened for their inhibitory effects on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. A resazurin assay was used to assess the antitrypanosomal and antileishmanial activities of the test compounds, whereas the antiplasmodial activity was evaluated through the SYBR Green I test. Moreover, the cytotoxicities of the test compounds were evaluated in Vero, Raw 264.7, and HepG-2 cells using a resazurin-based test, while their pharmacokinetic properties were predicted using the online tool, pkCSM. As a result, compound Y exhibited selective (selectivity index range: from 2.69 to >61.4; Vero, Raw 264.7, and HepG-2 cells) and broad-spectrum antiprotozoal activity against L. donovani promastigotes (IC₅₀: 12.4 µM), amastigotes (IC₅₀: 4.28 µM), P. falciparum (IC₅₀: 0.028 µM), and T. brucei brucei (IC₅₀: 0.81 µM). In addition, compound X inhibited the growth of P. falciparum (IC₅₀: 0.0052 µM) and T. brucei brucei (IC₅₀: 6.49 µM). In silico screening of the active antiprotozoal compounds revealed positive drug likeness scores, as none of the criteria for Lipinski’s rule were violated by these compounds. However, in-depth pharmacokinetic and mechanistic studies are warranted to support the discovery of novel antiprotozoal agents against malaria, leishmaniasis, and African trypanosomiasis by repurposing K⁺ channel blockers and DHFR inhibitors. Full article

Actinobacteria are known for their production of bioactive specialized metabolites, but they are still under-exploited. This study uses the “One Strain Many Compounds” (OSMAC) method to explore the potential of three preselected marine-derived actinobacteria: Salinispora arenicola (SH-78) and two Micromonospora sp. strains (SH-82 and SH-57). Various parameters, including the duration of the culture and the nature of the growth medium, were modified to assess their impact on the production of specialized metabolites. This approach involved a characterization based on chemical analysis completed with the construction of molecular networks and biological testing to evaluate cytotoxic and antiplasmodial activities. The results indicated that the influence of culture parameters depended on the studied species and also varied in relation with the microbial metabolites targeted. However, common favorable parameters could be observed for all strains such as an increase in the duration of the culture or the use of the A1 medium. For Micromonospora sp. SH-82, the solid A1 medium culture over 21 days favored a greater chemical diversity. A rise in the antiplasmodial activity was observed with this culture duration, with a IC₅₀ twice as low as for the 14-day culture. Micromonospora sp. SH-57 produced more diverse natural products in liquid culture, with approximately 54% of nodes from the molecular network specifically linked to the type of culture support. Enhanced biological activities were also observed with specific sets of parameters. Finally, for Salinispora arenicola SH-78, liquid culture allowed a greater diversity of metabolites, but intensity variations were specifically observed for some metabolites under other conditions. Notably, compounds related to staurosporine were more abundant in solid culture. Consequently, in the range of the chosen parameters, optimal conditions to enhance metabolic diversity and biological activities in these three marine-derived actinobacteria were identified, paving the way for future isolation works. Full article

Gracilioether M (6) and 11,12-dihydrogracilioether M (7), two polyketides with a [2(5H)-furanylidene]ethanoate moiety, along with known plakortone G (9) and its new naturally occurring derivative 9,10-dihydroplakortone G (8), were isolated from the Caribbean marine sponge Plakortis halichondrioides. The structures and absolute configuration of 6, 7, and 8 were characterized by analysis of HRESIMS and NMR spectroscopic data, chemical derivatization, and side-by-side comparisons with published NMR data of related analogs. Compounds 6 and 7 and a mixture of 8 and 9 were evaluated for cytotoxicity against MCF-7 human breast cancer cells. In addition, the in vitro antiplasmodial activity against Plasmodium berghei of these compounds was scrutinized using a drug luminescence assay. Full article

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, 21β-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 21β-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 (SI_Dd2 > 10) for the extract and fractions and most of the derived compounds. Of note, the limonoid mixture [21β-hydroxylbourjotinolone A (1a) + 21α-melianodiol (1b) + 21β-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. Full article

Sesquiterpenoids, an important class of natural products possessing three isoprene-derived units, are widely distributed across plants and have a variety of biological activities. All sesquiterpenoids are derived from farnesyl pyrophosphate (FPP), a biosynthesis precursor that can form various carbon skeletons. In order to provide a reference for further research and development of these compounds, this review focused on the increasing number of isolated and volatile sesquiterpenoids found to be produced by plants of the Meliaceae family between 1968 and 2023. The related articles were collected from SciFinder, Google Scholar, and PubMed. According to a literature review, several studies were started for more than 55 years on the plant’s stem barks, twigs, leaves, flowers, seeds, and pericarps, where approximately 413 sesquiterpenoid compounds from several groups such as eudesmane, aromadendrane, cadinane, guaiane, bisabolane, furanoeremophilane, humulene, germacrane, and oppositane-type were isolated and identified with some minor products. Additionally, the hypothetical route of sesquiterpenoids biosynthesis from this family was identified, and eudesmane-type was reported to be 27% of the total compounds. The antimicrobial, antidiabetic, antioxidant, antiplasmodial, antiviral, and cytotoxic activities of the isolated compounds and major volatile sesquiterpenoids constituent on essential oil were also evaluated. The result showed the fundamental of using the sesquiterpenoid compounds from the Meliaceae family in traditional medicine and the discovery of new drugs. Full article

Malaria is an infectious and parasitic disease caused by protozoa of the genus Plasmodium, which affects millions of people in tropical and subtropical areas. Recently, there have been multiple reports of drug resistance in Plasmodium populations, leading to the search for potential new active compounds against the parasite. Thus, we aimed to evaluate the in vitro antiplasmodial activity and cytotoxicity of the hydroalcoholic extract of Jucá (Libidibia ferrea) in serial concentrations. Jucá was used in the form of a freeze-dried hydroalcoholic extract. For the cytotoxicity assay, the(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) method with the WI-26VA4 human cell line was used. For the antiplasmodial activity, Plasmodium falciparum synchronized cultures were treated with serial concentrations (0.2 to 50 μg/mL) of the Jucá extract. In terms of the chemical composition of the Jucá extract, gas chromatography coupled to mass spectrometry measurements revealed the main compounds as ellagic acid, valoneic acid dilactone, gallotannin, and gallic acid. The Jucá hydroalcoholic extract did not show cytotoxic activity per MTT, with an IC₅₀ value greater than 100 µg/mL. Regarding the antiplasmodial activity, the Jucá extract presented an IC₅₀ of 11.10 µg/mL with a selective index of nine. Because of its antiplasmodial activity at the tested concentrations and low toxicity, the Jucá extract is presented as a candidate for herbal medicine in the treatment of malaria. To the best of our knowledge, this is the first report of antiplasmodial activity in Jucá. Full article

Despite considerable advances in medicine and technology, humanity still faces many deadly diseases such as cancer and malaria. In order to find appropriate treatments, the discovery of new bioactive substances is essential. Therefore, research is now turning to less frequently explored habitats with exceptional biodiversity such as the marine environment. Many studies have demonstrated the therapeutic potential of bioactive compounds from marine macro- and microorganisms. In this study, nine microbial strains isolated from an Indian Ocean sponge, Scopalina hapalia, were screened for their chemical potential. The isolates belong to different phyla, some of which are already known for their production of secondary metabolites, such as the actinobacteria. This article aims at describing the selection method used to identify the most promising microorganisms in the field of active metabolites production. The method is based on the combination of their biological and chemical screening, coupled with the use of bioinformatic tools. The dereplication of microbial extracts and the creation of a molecular network revealed the presence of known bioactive molecules such as staurosporin, erythromycin and chaetoglobosins. Molecular network exploration indicated the possible presence of novel compounds in clusters of interest. The biological activities targeted in the study were cytotoxicity against the HCT-116 and MDA-MB-231 cell lines and antiplasmodial activity against Plasmodium falciparum 3D7. Chaetomium globosum SH-123 and Salinispora arenicola SH-78 strains actually showed remarkable cytotoxic and antiplasmodial activities, while Micromonospora fluostatini SH-82 demonstrated promising antiplasmodial effects. The ranking of the microorganisms as a result of the different screening steps allowed the selection of a promising strain, Micromonospora fluostatini SH-82, as a premium candidate for the discovery of new drugs. Full article