The development of new molecules for the treatment of leishmaniasis is, a neglected parasitic disease, is urgent as current anti-leishmanial therapeutics are hampered by drug toxicity and resistance. The pyrrolo[1,2-b]isoquinoline core was selected as starting point, and palladium-catalyzed Heck-initiated cascade reactions were developed for the synthesis of a series of C-10 substituted derivatives. Their in vitro leishmanicidal activity against visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis was evaluated. The best activity was found, in general, for the 10-arylmethyl substituted pyrroloisoquinolines. In particular, 2ad (IC50 = 3.30 μM, SI > 77.01) and 2bb (IC50 = 3.93 μM, SI > 58.77) were approximately 10-fold more potent and selective than the drug of reference (miltefosine), against L. amazonensis on in vitro promastigote assays, while 2ae was the more active compound in the in vitro amastigote assays (IC50 = 33.59 μM, SI > 8.93). Notably, almost all compounds showed low cytotoxicity, CC50 > 100 μg/mL in J774 cells, highest tested dose. In addition, we have developed the first Perturbation Theory Machine Learning (PTML) algorithm able to predict simultaneously multiple biological activity parameters (IC50, Ki, etc.) vs. any Leishmania species and target protein, with high values of specificity (>98%) and sensitivity (>90%) in both training and validation series. Therefore, this model may be useful to reduce time and assay costs (material and human resources) in the drug discovery process.

Cissus incisa leaves have been traditionally used in Mexican traditional medicine to treat certain cancerous illness. This study explored the metabolomic profile of this species using untargeted technique. Likewise, it determined the cytotoxic activity and interpreted all data by computational tools. The metabolomic profile was developed through UHPLC-QTOF-MS/MS for dereplication purposes. MetaboAnalyst database was used in metabolic pathway analysis and the network topological analysis. Hexane, chloroform/methanol, and aqueous extracts were evaluated on HepG2, Hep3B, HeLa, PC3, A549, and MCF7 cancer cell lines and IHH immortalized hepatic cells, using Cell Titer proliferation assay kit. Hexane extract was the most active against Hep3B (IC₅₀ = 27 ± 3 μg/mL), while CHCl₃/MeOH extract was the most selective (SI = 2.77) on the same cell line. A Principal Component Analysis (PCA) showed similar profiles between the extracts, while a Venn diagram revealed 80 coincident metabolites between the bioactive extracts. The sesquiterpenoid and triterpenoid biosynthesis pathway was the most significant identified. The Network Pharmacology (NP) approach revealed several targets for presqualene diphosphate, phytol, stearic acid, δ-tocopherol, ursolic acid and γ-linolenic acid, involved in cellular processes such as apoptosis. This work highlights the integration of untargeted metabolomic profile and cytotoxic activity to explore plant extracts, and the NP approach to interpreting the experimental results.

Cissus incisa is used in traditional Mexican medicine to treat certain ailments, infectious or cancerous diseases. Excepting for our previous research, this species had no scientific reports validating its traditional use. In this study, we evaluated the antibacterial and cytotoxic properties of the sphingolipids and others phytocompounds isolated from C. incisa leaves to increase the scientific knowledge of the Mexican flora. The antibacterial activity was evaluated against Gram-positive and Gram-negative bacteria by the Microdilution method. Meanwhile, the cytotoxic potential was determined on six human cancer cells: PC3, Hep3B, HepG2, MCF7, A549, and HeLa; using an aqueous solution cell proliferation assay kit. A cell line of immortalized human hepatocytes (IHH) was included as a control of non-cancerous cells. Selectivity index (SI) was determined only against the hepatocellular carcinoma cell lines. The phytochemical investigation of C. incisa leaves resulted in the isolation and characterization of five compounds: 2-(2′-hydroxydecanoyl amino)-1,3,4-hexadecanotriol-8-ene (1), 2,3-dihydroxypropyl tetracosanoate (2), β-sitosterol-D-glucopyranoside (3), α-amyrin-3-O-β-D-glucopyranoside (4), and a mixture of cerebrosides (5). Until now, this is the first report of the sphingolipids (1), (5-IV) and (5-V). Only the compound (4) and cerebrosides (5) exhibited antibacterial activity reaching a MIC value of 100 μg/mL against Pseudomonas aeruginosa resistant to carbapenems. While, the acetylated derivate of (3), compound (3Ac) showed the best cytotoxic result against PC3 (IC50 = 43 ± 4 μg/mL) and Hep3B (IC50 = 49.0 ± 4 μg/mL) cancer cell lines. Likewise, (3Ac) achieved better SI values on HepG2 and Hep3B cell lines. This research reveals the importance of study medicinal plants, to identify bioactive molecules as sources of potential drugs. The presence of these compounds allows us to justify the use of this plant in traditional Mexican medicine.

Cada año, miles de toneladas de algas marinas arriban a las costas del Caribe a causa del Gran Cinturón de Sargazo del Atlántico (GASB, por sus siglas en inglés), el mayor florecimiento de la macroalga de este tipo del mundo, de hasta 8,850 km y un peso que ronda las 22 toneladas. Dichas playas, usualmente adornadas sólo por arena blanca y aguas turquesas, ahora se ven cubiertas por densas pilas en descomposición de macroalgas color pardo, conocidas coloquialmente como “sargazo”.

Background: Cissus incisa is a Vitaceae with a pantropical distribution. In northern Mexico, its leaves have traditionally been used to treat skin infections, abscesses and tumors. Despite its medicinal uses, few studies have been reported. Objective: The objective of this study is to summarize the phytochemical and biological studies carried out so far on the leaves of C. incisa, since this part of the plant is the one frequently used, and awaken scientific interest towards the plant. Methods: Since C. incisa was an undocumented species, most of the information comes from reports of our research group. Databases, books, and websites were also consulted. The information collected was organized and presented in a synthesized way. Plant name was checked with the database “The Plant List”. Results: 171, 260, and 114 metabolites were identified by UHPLC-QFTOF-MS in the hexane, chloroform/ methanol, and aqueous extracts, respectively. Fatty acyls, sphingolipids, sterols, glycerolipids, prenol lipids, and terpenes are common metabolites found in these extracts. 2-(2´-hydroxydecanoyl amino)-1,3,4-hexadecanotriol-8-ene, 2,3-dihydroxypropyl tetracosanoate, β-sitosterol, β-sitosterol-D-glucopyranoside, α-amyrin-3-O-β-D-glucopyranoside were also isolated and characterized. Extracts, phytocompounds and semi-synthetic derivatives showed antimicrobial activity against multi-drug resistant bacteria and various cancer cell lines. Results from Perturbation- Theory-Machine Learning-Information-Fusion model (PTMLIF), molecular docking, and vesicular contents assay identified potential targets on the cell membrane, suggesting an antibacterial mechanism of action for ceramides from C. incisa leaves. Conclusion: This review reports the efforts of the scientific community in authenticating species used in traditional medicine. Moreover, it gives a compendium of phytochemistry and the biological activities of the components from C. incisa leaves.