**1. Introduction**

Identifying lead compounds is one of the biggest challenges in drug discovery. Natural products (NPs) and their intricate molecular frameworks have a long tradition as valuable starting points for drug development (for example, artemisinins, taxol, camptothecin, and penicillins). To date, NPs remain a significant source of new compounds, providing a wide range of structural diversities with multiple privileged scaffolds for drug discovery either directly, semi-synthetically, or as a source of inspiration [1–5]. However, discovering new bioactive NPs is generally time-consuming and laborious. Only a few new NP drug pharmacophores have been found over the past 20 years, representing critical issues for NPs-driven lead discovery campaigns.

Mangrove forests are complex ecosystems widely distributed in tropical and subtropical estuaries or coastal intertidal zones. These forests contain diverse biological communities, including mangrove plants and numerous groups of microorganisms. The environment of the mangrove system harbors unique traits, for instance, high salinity, low oxygen, tidal gradients, high temperature, and excessively intense light, resulting in an active ecosystem with various microorganisms [1–5]. Mangrove-associated microorganisms have been demonstrated to be a reliable source of bioactive metabolites and have likewise drawn the attention of NP researchers [6–12]. A large number of structurally unusual and bioactive NPs have been discovered from the mangrove-associated microorganisms, including fungal and bacterial endophytes isolated from the mangrove plants' leaves, branches, and roots [13,14]. In addition, Mangrove sediments-derived microbes, a rich reservoir of NP diversity, could be utilized to explore new drugs [15].

The bioactive NPs solely from the true mangrove and semi-mangrove floras worldwide have been summarized in several review papers in 2010 [16,17]. However, the investigation of the mangrove ecosystem is mainly focused on the mangrove-associated microorganism

**Citation:** Wu, M.-J.; Xu, B.; Guo, Y.-W. Unusual Secondary Metabolites from the Mangrove Ecosystems: Structures, Bioactivities, Chemical, and Bio-Syntheses. *Mar. Drugs* **2022**, *20*, 535. https://doi.org/10.3390/ md20080535

Academic Editors: Wenhan Lin, Guoqiang Li and Jing Xu

Received: 28 July 2022 Accepted: 18 August 2022 Published: 20 August 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

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but less on the mangrove flora in recent years. Three comprehensive reviews have recently focused on the NPs from mangrove-associated fungi and mangrove sediments-derived microbes [6,14,15]. However, to our knowledge, no review has been published on the secondary metabolites with unusual skeletons from the mangrove ecosystem. They might merit the attention of chemists and biologists and could be a source of fresh pharmacophores with biological activity for the creation of drugs based on natural products.

In this review, we focus on the mangrove ecosystem-associated NPs featuring new carbon scaffolds, unique ring systems, or unusual functional moieties covering from 2010 to 2022. The structures, biological activities, biosynthesis, and total chemical syntheses of exampled unique compounds were included.

The references were searched using the following keywords as the subject search: natural products/secondary metabolites, mangrove, via Web of Science, Chemical Abstracts, and PubMed databases covering from 2010 to 2022, resulting in a collection of 134 unusual secondary metabolites. We classified them into two major families in terms of biological sources.

#### **2. Unusual Natural Products from Mangrove Flora**
