Indole Alkaloids from Psychoactive Mushrooms: Chemical and Pharmacological Potential as Psychotherapeutic Agents.

Neuropsychiatric diseases such as depression, anxiety, and post-traumatic stress represent a substantial long-term challenge for the global health systems because of their rising prevalence, uncertain neuropathology, and lack of effective pharmacological treatments. The approved existing studies constitute a piece of strong evidence whereby psychiatric drugs have shown to have unpleasant side effects and reduction of sustained tolerability, impacting patients' quality of life. Thus, the implementation of innovative strategies and alternative sources of bioactive molecules for the search for neuropsychiatric agents are required to guarantee the success of more effective drug candidates. Psychotherapeutic use of indole alkaloids derived from magic mushrooms has shown great interest and potential as an alternative to the synthetic drugs currently used on the market. The focus on indole alkaloids is linked to their rich history, their use as pharmaceuticals, and their broad range of biological properties, collectively underscoring the indole heterocycle as significant in drug discovery. In this review, we aim to report the physicochemical and pharmacological characteristics of indole alkaloids, particularly those derived from magic mushrooms, highlighting the promising application of such active ingredients as safe and effective therapeutic agents for the treatment of neuropsychiatric disorders.

Natural isoquinoline alkaloids: Pharmacological features and multi-target potential for complex diseases.

Complex diseases such as neurodegenerative disorders and cancer constitute a growing public health problem due to the rising incidence and lack in effective therapies. Since pharmacotherapy based on a single target has been insufficient for drug development in complex diseases, the emerging multi-target approach is a promising strategy for the search of new drug candidates. Plant-derived isoquinoline alkaloids comprise a vast source of multimodal agents with unique structural diversity, and variated range of pharmacological activities. This review offers an exhaustive compilation of the pharmacological relevance and multi-target potential of natural isoquinolines, emphasizing their features and promising activity in complex diseases such as Alzheimer, Parkinson, and Cancer. Selected examples were discussed in depth to illustrate the most relevant structural motifs and their possible relationship with the multimodal activity offering a comprehensive baseline in the search and optimization of isoquinoline scaffolds with polypharmacological potential for complex diseases.

Isoquinoline alkaloids from the roots of Zanthoxylum rigidum as multi-target inhibitors of cholinesterase, monoamine oxidase A and Aß1-42 aggregation.

Multifactorial neurodegenerative disorders such as Alzheimer's disease (AD) are considered a growing public health problem due the rising incidence and low effectiveness of current treatments [6]. Since pharmacotherapy based on a single target has been insufficient for drug development in complex diseases, the emerging multi-target approach is a promising strategy for the search of new anti-AD drug candidates. Herein described natural isoquinoline alkaloids were investigated for multi-target activity on key mechanisms associated with the AD's pathogenesis, i.e. cholinergic depletion, beta amyloid (Aß) aggregation and oxidative stress. Alkaloid isolation from root extract of Zanthoxylum rigidum was carried out using multi-step chromatography and TLC-bioautography against acetylcholinesterase (AChE) giving eight purified isoquinoline alkaloids. Isolated compounds were tested for inhibitory activity against cholinesterase (AChE and BChE), monoamine oxidase (MAO-A and B) and Aß aggregation. Our study revealed two benzophenanthridine alkaloids, nitidine (5) and avicine (7), as the most potent multi-target candidates. Both showed dual cholinesterase inhibition, being more active against AChE over BChE, with IC50 values in sub-micromolar range in AChE. Kinetic analysis with cholinesterase showed, that both compounds are reversible-mixed inhibitors, where avicine (7) presented highest potency with Ki values of 0.063 µM (EeAChE), 0.511 µM (HrAChE) and 0.123 µM (EqBChE). In addition, these alkaloids presented moderate Aß1-42 anti-aggregation activity and MAO-A inhibition with IC50 values between 0.5 and 2 µM. Our findings suggest that avicine (7) is a promising natural compound and multifunctional candidate representing a suitable starting point for the development of new therapeutic agents for Alzheimer's disease.

Metabolomic profiling of Zanthoxylum species: Identification of anti-cholinesterase alkaloids candidates.

The isolation of bioactive compounds from natural sources is a key step in drug discovery and development, however, this procedure is usually expensive and difficult due to the complexity and the limited amounts of the metabolites in the extracts. Thus, rational or targeting isolations are becoming more popular to reduce the bottlenecks in bioactive natural products research. In this study, we used a LC-MS-based metabolomic approach and biochemometric statistical tools (PCA and OPLS-DA) to identify potential anti-cholinesterase alkaloids predictors in Zanthoxylum genus (Rutaceae). For this purpose, 41 alkaloid extracts from nine Colombian Zanthoxylum species were screened by UHPLC-UV-HRMS and inhibitory activity against Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE). Based on the screening results, a multivariate statistical analysis (MVA) and selection of anti-cholinesterase candidates were performed using the S-plot from the OPLS-DA model. The supervised analysis (OPLS-DA) paring the anti-cholinesterase screening and LC-HRMS data showed at least 11 ChE inhibition markers which could have contributed in the differentiation of active and inactive extracts. The predictors were tentatively identified by comparing chromatographic retention times (Rt) and accurate mass and MS2 fragmentation patterns. In general, the inhibition markers correspond to four types of isoquinoline alkaloids: tetrahydroprotoberberines, protoberberines, dihydrobenzophenanthridines and benzophenanthridines. The most active extracts from Z. schreberi and Z. monophylum showed the highest presence of berberine and chelerythrine, previously reported as cholinesterase inhibitors. Thus, to validate the results of the OPLS-DA model, three alkaloids from the bark of Z. schreberi (identified as berberine, chelerythrine and columbamine) were bio-directed isolated, and all of them showed strong inhibition against both enzymes. These findings support our statistical models and contribute to the rational search of anticholinesterase alkaloids. Therefore, LC-MS-based metabolomic approach combined with chemometric statistical analysis are shown as useful tools for the isolation of targeted bioactive natural products, contributing to improve the research and development stages of lead compounds.

Anti-tubercular screening of natural products from Colombian plants: 3-methoxynordomesticine, an inhibitor of MurE ligase of Mycobacterium tuberculosis.

OBJECTIVES: New anti-mycobacterial entities with novel mechanisms of action are clinically needed for treating resistant forms of tuberculosis. The purpose of this study was to evaluate anti-tubercular activity and selectivity of seven recently isolated natural products from Colombian plants. METHODS: MICs were determined using a liquid medium growth inhibition assay for Mycobacterium tuberculosis H(37)Rv and both solid and liquid media growth inhibition assays for Mycobacterium bovis BCG. Escherichia coli growth inhibition and mammalian macrophage cell toxicity were evaluated to establish the degree of selectivity of the natural product against whole cell organisms. Enzymatic inhibition of ATP-dependent MurE ligase from M. tuberculosis was assayed using a colorimetric phosphate detection method. The most active compound, 3-methoxynordomesticine hydrochloride, was further investigated on M. bovis BCG for its inhibition of sigmoidal growth, acid-fast staining and viability counting analysis. RESULTS: Aporphine alkaloids were found to be potent inhibitors of slow-growing mycobacterial pathogens showing favourable selectivity and cytotoxicity. In terms of their endogenous action, the aporphine alkaloids were found inhibitory to M. tuberculosis ATP-dependent MurE ligase at micromolar concentrations. A significantly low MIC was detected for 3-methoxynordomesticine hydrochloride against both M. bovis BCG and M. tuberculosis H(37)Rv. CONCLUSIONS: Considering all the data, 3-methoxynordomesticine hydrochloride was found to be a potent anti-tubercular compound with a favourable specificity profile. The alkaloid showed MurE inhibition and is considered an initial hit for exploring related chemical space.