Ignacio Antonio Jiménez

Chagas disease and leishmaniasis, caused by the protozoan Trypanosoma cruzi and different Leishmania species, respectively, remain public health problems in developing regions due to high prevalence and the limited efficacy and safety of current treatments. Plant-derived natural products are emerging as a promising source of safer antikinetoplastid agents. The present work explores Argyranthemum frutescens as a source of antiparasitic compounds to identify new therapeutic candidates. To address this aim, a bioassay-guided fractionation of the ethanolic root extract from cultivated A. frutescens was carried out against kinetoplastids, including T. cruzi, L. amazonensis, and L. donovani. Polyacetylenes with leishmanicidal and trypanocidal activity were identified using this approach. Among them, compound 1 showed greater activity than the reference drug miltefosine against L. amazonensis and T. cruzi. Compound 1 showed activity against the amastigote stages of both parasites, surpassing the activity of the leishmanicidal reference drug. Notably, compound 1 showed a good selectivity index against the mammalian cell line. The findings indicated that the nature of the chemical group present at the propargyl–benzyl position plays a role in compound bioactivity. Subsequent assays revealed that this compound induces programmed cell death-related processes in T. cruzi and L. amazonensis, including ATP depletion, chromatin condensation, plasma membrane damage, accumulation of reactive oxygen species (ROS), and alterations in mitochondrial membrane potential (ΔΨm). Collectively, these findings highlight the potential of polyacetylenes as promising antikinetoplastid lead compounds and identify A. frutescens as a valuable natural source for the development of therapeutic agents against Chagas disease and leishmaniasis.

Natural products from plants have played an important role in cancer and neurodegenerative diseases. In this context, the root bark of Maytenus chiapensis (Celastraceae) was investigated to examine its chemical constituents and potential biological activities. Chromatographic separation of the root bark extract yielded a new Diels–Alder adduct (morenine) formed by a triterpenophenolic moiety derived from tingenone and a bicyclic guaiane-type sesquiterpene linked through a 1,4-dioxane bridge. In addition, eight previously reported Diels–Alder adducts—retusonine and cheiloclines A–D and F–H—were isolated, together with their biosynthetic precursors, the quinone-methide triterpenoids (QMTs) pristimerin and tingenone. Structural elucidation was achieved through detailed 1D and 2D NMR spectroscopic analyses. The adducts were tested for cytotoxicity against six cancer cell lines (A549, SW1573, MIA PaCa-2, T-47D, HeLa, and WiDr cell lines), showing moderate-to-low activity compared with their precursors. Continuous live cell imaging identified apoptosis and vacuole formation as the main modes of action of pristimerin in SW1573 cells. Moreover, acetylcholinesterase inhibition assays revealed that cheiloclines B–D, F, and H exhibited up to 50% inhibition. These findings reinforce the potential of Celastraceae species as a source of unique and complex compounds and enhance our understanding of their therapeutic potential.

Current therapies for Primary Amoebic Meningoencephalitis (PAM) present several limitations; consequently, there is an urgent need to develop new therapeutic agents. In this regard, we undertook bioassay-guided isolation of Mentha rotundifolia leaves which allowed the identification of ursolic acid (1) as the main bioactive metabolite against two ATCC strains of Naegleria fowleri (ATCC^® 30808^TM and ATCC^® 30215^TM). Moreover, ten ursolic acid derivatives (2–11) were synthesized through esterification and nucleophilic substitution to obtain halo or amino ester derivatives. Among these derivatives, compound 7 exhibited the highest activity against the N. fowleri ATCC^® 30808^TM strain with an IC₅₀ value of 28.66 µM, whereas compound 10 showed the top activity against the N. fowleri ATCC^® 30215^TM strain with an IC₅₀ of 7.61 µM, surpassing the efficacy of the reference drug, miltefosine. Both compounds, 7 and 10, showed a good selectivity index and hence low toxicity in vitro. Structure–activity relationship studies revealed that the type of acylating agent played a crucial role in the activity. Furthermore, both compounds induced autophagy and apoptosis-like processes in both treated N. fowleri strains. These results highlight the potential of ursolic acid-related triterpenoids as drug scaffolds and identify M. rotundifolia as a promising natural source of amoebicidal agents against PAM.

Natural products have long been recognized as invaluable resources in drug discovery. Essential oils have attracted widespread attention due to their broad spectrum of biological activities. Herein, we report the anti-kinetoplastid activity of Aloysia citrodora leaf essential oil through a bioassay-guided fractionation method against the etiological agents of Chagas disease and leishmaniasis. This approach has led to the isolation and structural identification of compound 1 (citral) as the main active constituent, with IC₅₀ values of 8.47 μM against Leishmania amazonensis and 12.90 μM against Trypanosoma cruzi. In addition, eight compounds (2–9) were synthesized and evaluated. Among these, citral 2,4-dinitrophenylhydrazone (9) exhibited the highest anti-kinetoplastid activity, with an IC₅₀ value of 10.62 μM against L. amazonensis, displaying a similar biological profile to citral and the reference drug. Structure–activity relationship studies revealed that the type of Schiff base and acylating agent played a crucial role in the activity. Mechanism of action studies demonstrated that compound 9 directly targets the apoptotic pathway, inducing programmed cell death through selective pathway inhibition. This work underscores the potential of A. citrodora essential oil and its compounds as prospective therapeutic leads against neglected tropical diseases.

Leishmaniasis and Chagas disease are parasitic diseases considered to be among the most important neglected diseases, with implications for both developed and developing countries. Currently, there are no effective therapeutic treatments for these diseases due to challenges in drug administration, high toxicity, high costs, and drug resistance. In this study, a series of eleven thymol derivatives were designed, synthesized, and evaluated for their in vitro kinetoplastid activity against Leishmania amazonensis and Trypanosoma cruzi, as well as their cytotoxicity against a murine macrophage cell line. The most active compounds, thymol anysoate (9) and thymol picolinate (10), displayed the highest kinetoplastid activity with IC₅₀ values of 22.87 and 25.16 µM against L. amazonensis and T. cruzi, respectively. Notably, both compounds demonstrated an excellent selectivity index against the mammal cell line. Structure–activity relationship studies revealed that the ester group plays a crucial role in activity. The most promising derivatives, 9 and 10, activate autophagy and apoptosis-like processes in the treated cells. Atomic force microscopy observations showed that derivative 9 induces the formation of cytoplasmic vacuoles, indicating an autophagic process, and drug-likeness analysis revealed that it meets all the pharmacokinetic criteria. Overall, these results highlight derivative 9 as a potential lead compound for the development of new drugs for the treatment of Trypanosomatidae infections and warrants further studies to elucidate the cell death cascade involved.

Plant-derived biopesticides are emerging as a promising and popular alternative for promoting cleaner and safer agricultural practices. The present work aims to explore Argyranthemum frutescens (Asteraceae) as a source of botanical pesticides and to validate this through a cultivation process. To this task, a bioassay-guided fractionation of the ethanolic root extracts from both wild and cultivated A. frutescens on phytopathogenic fungi of Botrytis cinerea, Fusarium oxysporum, and Alternaria alternata was conducted. This approach led to the identification of polyacetylenes with higher potency than commercial fungicides. Specifically, compounds 3 (capillin) and 5 (frutescinone) showed more than 90% growth inhibition at 0.05 mg/mL concentration on B. cinerea, while compounds 2 (capillinol) and 3 were also more active than positive controls, Fosbel-Plus and Azoxystrobin, against F. oxysporum. The structures of the isolated polyacetylenes (1–6, 9, and 10) and alkamides (7, 8, and 11) were determined through spectroscopic analysis, and the absolute configuration of stereocenter C1 of compounds 1, 2, 4 and 9 was determined by NMR-spectroscopy with (R)-(-)-α-methoxy-phenylacetic as a chiral derivatizing agent, and biogenetic considerations. Overall, this study supports the potential of polyacetylenes as promising agrochemical lead compounds against phytopathogens, and validates A. frutescens cultivation as a viable source of biopesticides.