**2. Contributions**

Several original papers included in this Special Issue involve the search for new antibacterial and antifungal agents, mainly from secondary metabolites, their derivatives and essential oils of di fferent plant species. Essential oils are a mixture of volatile compounds, mainly mono-, di- and sesquiterpenes, with high commercial value and a wide range of applications [19,40].

*Piper caldense* (Piperaceae family) is popularly used for the treatment of snakebites, stomach problems and as a sedative [41]. The research presented by Bezerra et al. [42] shows that essential oils from *P. caldense* leaf are composed, in major proportions, by sesquiterpenes such as caryophyllene oxide, spathulenol, γ-cadinene and bicyclogermacrene. Although the essential oils do not show antifungal activity against *Candida albicans*, they exhibit a synergistic e ffect with the antifungal fuconazole, which increase their activity when used combined. This modulator e ffect is not observed at the highest concentration. The ability of essential oils to cause complete inhibition of the hyphae prolongation was also demonstrated, being an e ffect superior to fuconazole [42], which suggests their application as an adjuvant in antimicrobial formulations.

*Helianthus annus* (Asteraceae, sunflower) has been used as a traditional medicine to treat a variety of ailments, such as rattlesnake, spider, snake and scorpion bites, fevers [43,44], food poisoning [45], burning sensation in the vagina and worms in the ears [46]. Lawson et al. [47] report the chemical composition and antifungal activity of essential oils from the aerial parts of two cultivars of *H. annuus*, "Chianti" and "Mammoth", and wild-growing *Helianthus strumosus*. Analysis of these essential oils shows they are qualitatively similar and dominated by monoterpenes, in particular sabinene, α-pinene, β-pinene and limonene. The antifungal activity of essential oils and their main constituents were evaluated against three opportunistic pathogenic fungal species, *Aspergillus niger*, *Candida albicans* and *Cryptococcus neoformans*, which mainly a ffect immunocompromised patients. The essential oils of *H. annus* "Chianti" and *H. strumosus* are the most active against *C. neoformans* and the authors consider that the activity is due to both enantiomers of pinene.

Carvacrol is a usual essential oils constituent, that exhibits activity against *Penicillium digitatum*, a citrus crop fungal which causes significant economic losses [48], but whose mechanism of action is not completely clarified. Using an innovative approach, metabolomics based on 1H-NMR analysis, Wan et al. [49] determine the changes introduced into the *P. digitatum* metabolism and its energetic balance when this fungus is treated with carvacrol. The results show this compound induces ROS production on *P. digitatum*, which mainly disturbs the energy production by a decrease in glycolysis followed by an augmentation in gluconeogenesis involving mainly alanine, aspartate and glutamate metabolism.

Phenolic nor-triterpene are described in the literature as antibacterial agents against Gram-positive bacteria [50–52]. Moujir et al. [53] report the antimicrobial activity of five natural phenolic nor-triterpenes, isolated from *Maytenus blepharodes* and *Maytenus canariensis*, and four pristimerin derivatives synthesized. The most active compound was the derivative 6α-hydroxy-2,3-diacetoxy-pristimerol which is more active than the positive control cephotaxime against spore-forming bacteria and *Staphylococcus epidermidis*. A comprehensive structure/activity relationship (SAR) study was performed with the aim of the rational design of antimicrobial agents based on the phenolic nor-triterpene scaffold.

In addition to an application as antimicrobials, natural compounds, in pure form or as a mixture like essential oils, are also investigated as therapeutic agents with a potential application on other health problems like aging-associated diseases, cancer, diabetes or wounds.

*Portulaca oleracea* is used to alleviate a wide range of illnesses [54] and the extracts of this plant are known to possess a strong in vivo antioxidant capacity [55,56]. Based on the potent antioxidant activity of natural compounds oleracones isolated from this plant, Yoon et al. [57] carried out the synthesis of oleracones D–F and evaluated their lifespan extension properties using the nematode *Caenorhabditis elegans* as the experimental aging model. The oleracone E was the most active to extend the lifespan of nematodes. Therefore, this compound should be considered in the development of anti-aging formulations.

Another study where the antioxidant activity of natural compounds was assessed is proposed by Tungmunnithum et al. [58]. They optimize and validate a new green and fast microextraction procedure to obtain a phenolic acids-rich fraction from almond (*Prunus dulcis*) cold-pressed oil residue. The authors identified and quantified some of the most abundant constituents, protocatechuic, *p*-hydroxybenzoic, chlorogenic and *p*-coumaric acids and evaluated the antioxidant activity of this fraction. They sugges<sup>t</sup> it as a source of antioxidant natural compounds with applications in food preservation, as medicine and in cosmetic preparations. Thus, it is given a contribution to value a very abundant by-product of the almond oil industry.

*Salvia miltiorrhizae* is one of the well-known traditional herbal medicines that has increased its scientific interest for its remarkable bioactivity against cardiovascular disease, renal damage, tumor angiogenesis and tumor cell invasion [59,60]. Kang et al. [61] evaluate a series of compounds isolated from *S. miltiorrhizae* Radix such as tanshinone IIA, rosmarinic acid, salvianic acid A, salvianolic acid B and caffeic acid for their cytotoxic activity and mode of action against the HCT-116 cell line (human colorectal cancer, one of the most commonly diagnosed malignant diseases [62]). Only a terpenoid, tanshinone IIA, shows an inhibitory effect on cell survival (IC50 61.6 μg/mL). Morphological changes observed by Hoechst staining, an increase in cleaved caspase-7 and -8 and Bax expression as well as a decrease in Bcl-2 show this compound as an inducer of apoptosis which may be a useful chemotherapy strategy for patients with colorectal cancer.

The flavonoid-type compounds named chalcones and flavanones are natural isomeric compounds which exhibit a broad range of patented therapeutic applications [63]. Since they are chemically very labile, chalcones and flavanones are also excellent scaffolds to medicinal chemistry and development of new drugs [64–66]. In this context, the optimization of the aldol condensation synthesis route by using unexplored bases to prepare hydroxylated and methoxylated chalcones and flavanones proposed by Rosa et al. [67] is well come. The application of the synthesized compounds as cytotoxic, antioxidant, antibacterial and anticholinesterase agents were evaluated, and SAR are discussed. The SAR study showed the same substituent group can cause an opposite effect on the level of different biological activities, given as a significant contribution to better understand the medicinal chemistry of these compounds.

Plants are also considered to be sources of natural compounds with antidiabetic activity, as shown by Numonov et al. [68]. They studied the chemical composition of essential oils from *Prangos pabularia* roots and describe it as a potent protein tyrosine phosphatase 1B (PTP-1B) inhibitor. Additionally, the authors used docking studies and experimental procedures to indicate coumarin osthole, one of the most abundant constituents, as probably responsible for the potent PTP-1B inhibition, a stronger effect than the positive control, and thus support the use of *P. pabularia* roots' essential oil and osthole as antidiabetic agents.

Propolis and honey are valuable natural products with several health applications already described in the literature [69,70]. However, the properties and chemical composition of these natural products significantly depend on several factors such as the plant species used in their production [71]. Using different samples of Portuguese honey, propolis and a mixture of both, Afonso et al. [72] present an original study where the antioxidant, anti-inflammatory and wound-healing activities of ethanolic extracts of these samples were evaluated. The study demonstrates that propolis extracts have higher phenolic compounds and flavonoid contents than honey extracts. On the other hand, the mixtures of honey/propolis exhibit, in general, a significant wound-healing effect, but the propolis extract 2 (propolis from the red-honey box) is the most active sample, this activity being related to its high antioxidant and anti-inflammatory effect.

The Special Issue also includes two review articles where the applications of natural sesquiterpene lactones and rosmarinic acid as potential medicines are reviewed.

Moujir et al. [73] highlight ten natural sesquiterpene lactones, alantolactone, arglabin, costunolide, cynaropicrin, helenalin, inuviscolide, lactucin, parthenolide, thapsigargin and tomentosin, critically discussing the results of in vivo studies and clinical trials involving these compounds. The work demonstrates the enormous potential of these compounds in the development of new drugs especially for the treatment of oncological and inflammatory diseases. Their application as antifungal, antitrypanosomal and analgesic agents is also discussed, although the most surprising results are related to their sensitizing effect to the action of some clinical drugs, which means their application in combination therapy. Some synthetic derivatives of these sesquiterpene lactones are also highlighted, mainly because they demonstrate very significant improvements in pharmacokinetics and selectivity, compared with the original compounds.

In its turn, Nadeem et al. review the therapeutic value of rosmarinic acid [74]. This natural phenolic compound, very abundant on several edible species such as *Rosmarinus <sup>o</sup>*ffi*cinalis*, *Ocimum tenuiflorum* and *Thymus mastichina*, exhibits a wide range of biological effects. The authors [74] present and discuss scientific evidence of its antitumor, anti-inflammatory, antimicrobial, antidiabetic, antioxidant, anti-aging, cardio and nephroprotective effects. Further, the mechanism of action is discussed, although the authors identified this aspect as the knowledge gap that needs further investigation.

This *Applied Sciences* Special Issue emphasizes natural compounds' potential for distinct applications. The authors, from all over the world, contribute with valuable manuscripts to this Special Issue, strengthening the high value of natural compounds and the dynamism of this research field.

**Author Contributions:** A.M.L.S. and L.M. conceived, designed and wrote the editorial. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by FCT–Fundação para a Ciência e a Tecnologia, the European Union, QREN, FEDER, COMPETE, by funding the cE3c centre (UIDB/00329/2020) and the LAQV-REQUIMTE (UIDB/50006/2020) research units, and by the Spanish Ministry Science and Research (MINECO RTI2018-094356-B-C21).

**Acknowledgments:** Thanks are due to the University of Azores and University of La Laguna.

**Conflicts of Interest:** The authors L.M. and A.M.L.S. declare no conflict of interest.
