The search for novel antimycobacterial drugs is a matter of urgency, since tuberculosis is still one of the top ten causes of death from a single infectious agent, killing more than 1.4 million people worldwide each year. Nine Amaryllidaceae alkaloids (AAs) of various structural types have been screened for their antimycobacterial activity. Unfortunately, all were considered inactive, and thus a pilot series of aromatic esters of galanthamine, 3-O-methylpancracine, vittatine and maritidine were synthesized to increase biological activity. The semisynthetic derivatives of AAs were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Ra and two other mycobacterial strains (M. aurum, M. smegmatis) using a modified Microplate Alamar Blue Assay. The most active compounds were also studied for their in vitro hepatotoxicity on the hepatocellular carcinoma cell line HepG2. In general, the derivatization of the original AAs was associated with a significant increase in antimycobacterial activity. Several pilot derivatives were identified as compounds with micromolar MICs against M. tuberculosis H37Ra. Two derivatives of galanthamine, 1i and 1r, were selected for further structure optimalization to increase the selectivity index.

• Keywords
• 3-O-methylpancracine, Amaryllidaceae, analogues, antimycobacterial activity, cytotoxicity, galanthamine, tuberculosis,
• MeSH
• Amaryllidaceae Alkaloids adverse effects   chemical synthesis   pharmacology   MeSH
• Anti-Bacterial Agents adverse effects   chemical synthesis   pharmacology   MeSH
• Hep G2 Cells MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amaryllidaceae Alkaloids MeSH
• Anti-Bacterial Agents MeSH

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1-20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.

• Keywords
• Alzheimer’s disease, amaryllidaceae alkaloid, butyrylcholinesterase, docking studies, norbelladine-type,
• MeSH
• Acetylcholinesterase chemistry   MeSH
• Amaryllidaceae Alkaloids chemistry   MeSH
• Butyrylcholinesterase chemistry   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Humans MeSH
• Tumor Cells, Cultured MeSH
• Neuroblastoma drug therapy   pathology   MeSH
• Computer Simulation MeSH
• Cell Proliferation MeSH
• Molecular Docking Simulation * MeSH
• Tyramine analogs & derivatives   chemistry   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Evaluation Study MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Amaryllidaceae Alkaloids MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• norbelladine MeSH Browser
• Tyramine MeSH

Pancracine, a montanine-type Amaryllidaceae alkaloid (AA), is one of the most potent compounds among natural isoquinolines. In previous studies, pancracine exhibited cytotoxic activity against diverse human cancer cell lines in vitro. However, further insight into the molecular mechanisms that underlie the cytotoxic effect of pancracine have not been reported and remain unknown. To fill this void, the cell proliferation and viability of cancer cells was explored using the Trypan Blue assay or by using the xCELLigence system. The impact on the cell cycle was determined by flow cytometry. Apoptosis was evaluated by Annexin V/PI and by quantifying the activity of caspases (-3/7, -8, and -9). Proteins triggering growth arrest or apoptosis were detected by Western blotting. Pancracine has strong antiproliferative activity on A549 cells, lasting up to 96 h, and antiproliferative and cytotoxic effects on MOLT-4 cells. The apoptosis-inducing activity of pancracine in MOLT-4 cells was evidenced by the significantly higher activity of caspases. This was transmitted through the upregulation of p53 phosphorylated on Ser392, p38 MAPK phosphorylated on Thr180/Tyr182, and upregulation of p27. The pancracine treatment negatively altered the proliferation of A549 cells as a consequence of an increase in G1-phase accumulation, associated with the downregulation of Rb phosphorylated on Ser807/811 and with the concomitant upregulation of p27 and downregulation of Akt phosphorylated on Thr308. This was the first study to glean a deeper mechanistic understanding of pancracine activity in vitro. Perturbation of the cell cycle and induction of apoptotic cell death were considered key mechanisms of pancracine action.

• Keywords
• Amaryllidaceae alkaloids, antiproliferative activity, apoptosis, cell cycle arrest, cytotoxicity, pancracine,
• MeSH
• Adenocarcinoma of Lung pathology   MeSH
• Alkaloids isolation & purification   pharmacology   MeSH
• Amaryllidaceae chemistry   MeSH
• Apoptosis drug effects   MeSH
• A549 Cells MeSH
• Hep G2 Cells MeSH
• Antineoplastic Agents, Phytogenic isolation & purification   pharmacology   MeSH
• Heterocyclic Compounds, 4 or More Rings isolation & purification   pharmacology   MeSH
• Leukemia pathology   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Cell Line, Tumor MeSH
• Lung Neoplasms pathology   MeSH
• Cell Proliferation drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alkaloids MeSH
• Antineoplastic Agents, Phytogenic MeSH
• Heterocyclic Compounds, 4 or More Rings MeSH
• pancracine MeSH Browser