Alkaloids and Other Nitrogen-Containing Derivatives

The classical definition of alkaloids describes this class of secondary metabolites as chemical structures containing nitrogen as part of a heterocyclic, with alkaline character, characterized by complex structure and limited distribution, mainly in the plant kingdom. The modern history of alkaloids starts in the early nineteenth century as figured by two milestone dates, 1803 when Derosne described the isolation of a mixture containing narcotin and morphine from opium, and 1819 when the chemist Meissner delivered an operative definition of the term alkaloid. They have been observed with sporadic distribution in bacteria, fungi, Pteridophytae and Gymnophytae, while they are mainly represented in higher plants and within Angiosperms, particularly in selected families, such as Annonaceae, Lauraceae, Loganaceae, Menispermaceae, Papaveraceae, Ranuncolaceae, Rubiaceae, Rutaceae, Solanaceae and others. Frequently, a plant activates selectively a metabolic pathway that produces a mixture of multiple but structure-related alkaloids. Sometimes, dozens may be with a restricted number representing the majority of the total content. The latter parameter could change significantly as a result of a plethora of many factors, including the plant organ, seasonal variations, phenological status and others. As general rules, the alkaloids are segregated in the form of salt inside cell vacuole or sometimes in laticifer, mainly through the superficial tissues, supporting the hypothesis of their biological involvement in plant-environment interactions. 

Morphine, an alkaloid isolated from the opium poppy, has been widely used as an analgesic, and has been a fascinating synthetic target of organic chemists. All these opioid drugs produce their biological actions through three receptor types, µ, δ, and κ, belonging to the G-protein-coupled receptor family. Currently, used opioid analgesics also share a number of severe side effects, limiting their clinical usefulness. The chemically highly versatile structure of morphine and its related natural alkaloids has continuously engaged the interest of pharmaceutical and medicinal chemistry research, aiming for the synthesis and identification of numerous semi- and synthetic opioid ligands as safer therapeutic agents or with novel therapeutic properties and with lesser unwanted side effects with the final goal to reduce complications and to improve patient compliance. This review provides the first total synthesis reported in 1952 and focuses on representative examples of various derivatives and interesting approaches for the development of structurally correlated molecules with substitutions at different rings position leading to preclinical and clinically valuable opioids.

Neurodegenerative disorders, such as Alzheimer’s and Parkinson’s, are very complex diseases, whose treatment and prevention are still very problematic to date. The search for new potential treatments is always a current topic. In this context, the discovery of molecules with a dual-targeting action against both MAO-B enzyme and A2A receptor has been largely pursued in recent years, considering their involvement in the etiological process of these diseases. In particular, caffeine, an alkaloid largely present in beverages and foods, has been shown to possess beneficial effects in the prevention/treatment of neurodegenerative disorders. Moreover, in vitro assays have confirmed its interaction with the MAO-B enzyme and A2A receptor, stimulating the synthesis of caffeine chemical derivatives that can strongly act against these two targets. In this chapter, several classes of caffeine derivatives have been discussed, with particular attention on their synthesis and (dual) biological activity of MAO-B enzyme and A2A receptor.

The alkaloid piperine has always attracted the interest of pharmaceutical botanists for its biological activities and pharmacokinetics-modulating properties. It is currently used in combination with other compounds for the treatment of several diseases. Starting from its peculiar structure, medicinal chemists have explored the chemical space around the amide portion, the conjugated double bond chain and the benzodioxole ring. This approach led to a large plethora of derivatives, which diversified the properties of the parent compound or improved its potency against specific targets or biological systems. In this chapter, several classes of piperine derivatives have been discussed and classified according to the proposed therapeutic use, with a particular attention on their structure-activity relationships and biological activity values.

Cancer is the second leading cause of death globally, in which factors, such as tobacco, radiation, and obesity contribute to this alarming data. Among the available pharmacotherapy, natural products, such as noscapine, have historical evidence in treating this disease, showing promising results aimed at inhibiting tubulin. In this context, this remarkable molecule has been tested as a conjugated drug in treating the COVID-19 pandemic. In this chapter, we demonstrate noscapine structurally-related compounds, analyzing them based on SAR studies, and discuss the most promising results reported so far. 

Biogenic amines (BAs) and amino acids (AAs) are essential components of every living organism, being the precursors of vital compounds, such as hormones, alkaloids, nucleic acids and proteins, among others. They are directly involved in many metabolic processes, growth regulation, cellular transmission and diseases. A plethora of biological substrates yet to be fully identified are the targets of BAs and AAs. The Carbonic Anhydrases (CAs; EC 4.2.1.1) are listed among them. These metalloenzymes are virtually expressed in every living organism, with eight genetically distinct families described to date. CAs main biological function is represented by CO2 hydration catalysis. Amino acids and amines are usually reported as efficient CA activators and are thus potentially useful for therapeutic purposes in aging and neurodegenerative diseases as well as tissue engineering. To date, polyamines are the only exception as they were identified to act as CA inhibitors. Here, we will review the main contributions in the field covering the effects of such crucial molecules on CAs expressed in various organisms (mammals, fungi, protozoan, bacteria and archaea). Synthetic analogues of amines and amino acids obtained from various drug design approaches, will also be considered. 

Plasmodium species are responsible for a high incidence of cases and resistance, even with several approved drugs. Quinoline derivatives are recognized as a source of active compounds, where tafenoquine has been recently approved. Cases of resistance and the indiscriminate use of anti-malarials against COVID-19 have negatively contributed to eradicating this disease. In this context, modifications at 2- or 4-amino positions from the quinoline scaffold or even its metal complexes have shown promising advances in the field, especially against resistant strains, such as 3D7, W2, D10, Dd2, K1 , and FCR-3. In this chapter, we discussed all aspects involving such compounds, presenting their results based on SAR analysis and recent contributions/advances involving this classic scaffold arising from nature.