**1. Introduction**

Nature Aided Drug Discovery (NADD) represents the most ancient approach in finding new active compounds for fighting human diseases, and still today it plays a crucial role in drug discovery [1]. New chemical entities (NCE) from natural derivation represent a relevant slice among the drugs approved by Food and Drug Administration (FDA) and the European Medicines Agencies (EMA) for commercialization and administration on humans [2]. More than half the total antiinfective drugs approved in the last forty years resulted from a NADD approach and a similar trend can be observed for anticancer drugs, where 41% of them derived from natural sources and only 16% are classifiable as totally synthetic small molecules [2]. Moreover, the Global Herbal Medicine Market Size is expected to increase to USD 129 billion by 2023, according to Market Research Future [3].

The success of NADD finds its main reason in the wider and heterogeneous chemical space covered by natural products whether compared with synthetic derivatives. The 83% of the chemical scaffolds found in natural compounds are unique and absent in synthetic NCE, due to the lack of commercially available synthons or cumbersome and prohibitive synthetic procedures [4]. Thus, the screening of libraries of compounds derived from natural sources still remains a worthy procedure for the identification of new and unexplored NCE. Besides, marine sources or lichens are still almost uninvestigated and might therefore represent an inestimable treasure of new potential drugs [5–7].

The natural compounds of interest in NADD are secondary metabolites that are not directly involved in the essential functions of the cell cycle and duplication processes and are characterized by high structural variability. From a structural standpoint, they are classified into alkaloids, terpenoids, saponins, lignans, flavonoids, and tannins [8]. Secondary metabolites are produced in different amounts for vexillary functions or defensive responses to biotic or abiotic stress being involved in the system of plant defense [9]. For this reason, specific secondary metabolites may be considered as markers of the plant health and may be used to evaluate the quality of the selected natural matrix and the effects that the environmental factors have on it. The evaluation of their content in natural sources, as well as their recovery, require the exploitation of ad hoc extractive procedures since secondary metabolites are mainly present in the intracellular domain. Thus, appropriate extraction procedures involve the rupture of the cell wall and cellular membranes, thus favoring the passage of the secondary metabolites into the extraction solvent, from which they can be recovered.

Over the years different protocols and techniques have been developed for the extraction of metabolites from natural matrices, named Solid–Liquid Extraction (SLEs). SLEs are classified in conventional (or traditional) and non-conventional (or innovative) methodologies [10]. In conventional methodologies, SLE is performed by heating the natural source with conventional heating sources (i.e., flame, heating plate, or mantle) in the presence or not of solvent and with or without stirring. Examples of conventional methodologies are maceration (digestion, infusion, and decoction), percolation, and Soxhlet or steam distillation. Solvents, or generally mixtures of solvents, with wide grades of polarity such as methanol, ethanol, acetone, ethyl acetate, trichloromethane, hexane, *etc*. are employed. Nevertheless, conventional extraction methods usually require a large volume of solvents, long extraction time, and high temperature. Such harsh extraction conditions may lead to thermal or chemical degradation of the metabolites, thus resulting in a low yield of the final extract. Moreover, the upscaling at an industrial level would be impracticable, owing to energy consumption, technological inaccessibility, and environmental considerations [11]. Conversely, non-conventional methodologies exploit innovative chemical–physical principles and cutting-edge technologies to facilitate the extractive procedures and the recovery of the product of interest from the natural source. Varied energy sources and extractive principles may be exploited and, therefore, specific equipments are needed. Microwave-assisted Solid Extraction (MASE), ultrasound-assisted extraction (UAE), pressurized solvent extraction (PLE), and supercritical fluid extraction (SFE) are the most frequently non-conventional methodologies extensively used for NADD [11].

In this chapter, the potential of microwave-assisted irradiation for the extraction of secondary metabolites from plants, and natural resources in general, will be discussed, with a special focus on recent applicative examples of the most representative chemical classes.
