**4. Conclusions**

Fungal metabolites are an unparalleled pool for pharmaceutical lead discovery. Sesquiterpenoids involving the bergamotane skeleton have been separated from various sources, including fungi. In the current work, 97 bergamotane sesquiterpenoids were reported from various fungal species derived from different sources, including endophytic (24 compounds), mushroom (21 compounds), sea mud (14 compounds), sea sediment (13 compounds), deep-sea deposit (8 compounds), and sponges (3 compounds) (Figure 11).

**Figure 11.** Number of bergamotane sesquiterpenoids reported from fungi derived from various sources. End.: endophytic; Mus.: mushroom; SeaM.: sea mud-derived; SeaS.: sea sedimentderived; SeaD.: sea deposit-derived; Mus.D: mushroom-derived; Cult.: cultured; So.: soil-derived; Sp.D.: sponge-derived; Li.D.: lichen-derived; Sd.D.: sheep dung-derived; LeL.D.: leaf litter-derived; Fr.D.: fruit-derived.

The majority of compounds have been reported from *Paraconiothyrium* (25 compounds), *Craterellus* (23 compounds), and *Eutypella* (12 compounds) species (Figure 12). Interestingly, many of these metabolites normally occurred as inseparable mixtures. These metabolites were assessed for diverse bio-activities. It is obvious that cytotoxic evaluation accounts for the largest proportion of biological assessments, where they had weak or no effectiveness on the tested cell lines. On the other hand, there are limited reports on their phytotoxic, plant growth regulation, antimicrobial, anti-HIV, cytotoxic, anti-inflammatory, pancreatic lipase inhibition, immunosuppressive, and antidiabetic activities. Therefore, this suggested more potential for trying other types of pharmacological effectiveness. Victoxinine (**40**) and prehelminthosporolactone (**39**) displayed potential phytotoxic capacities; therefore, they could be utilized as bioherbicides or as lead metabolites for synthesizing more efficacious phytotoxic compounds against various weeds. Pinthunamide (**44**), ampullicin (**91**), isoampullicin (**92**), and dihydroampullicin (**93**) were found to selectively promote the root growth. However, the phytotoxic and plant growth promotion potential should be transferred from laboratory experiments into field settings for assessing the environmental influences on these activities. Purpurolide F (**87**) had potent pancreatic lipase inhibition potential that could be a viable candidate as a pancreatic lipase inhibitor for further clinical development. Massarinolin B (**61**) had prominent immunosuppressive potential, suggesting further in vivo and mechanistic investigations for the development of this metabolite as an immunosuppressant. In silico studies for the reported metabolites that have not been tested or have had no noticeable effectiveness in the estimated activities could be a possible area of future research. Moreover, synthesis and structural modifications of these metabolites may produce more potential and useful tags of these metabolites through click chemistry, which is a new approach for synthesizing drug-like molecules that can boost the drug discovery process.

**Figure 12.** Bergamotane sesquiterpenoids from various fungal species.

Biogenetically, these metabolites are generated from acyclic farnesyl-diphosphate, which undertakes various condensation and rearrangement reactions. This work could be a beneficial reference for researchers studying this class of fungal metabolites. Several strategies, including co-culture, molecular and epigenetic manipulations, OSMAC (one strain many compounds), heterologous gene expression, and inter-species cross-talk approaches could be successively employed to access undescribed natural metabolites from silent biosynthetic pathways. It was found that the selective epigenetic target manipulation utilizing small molecule inhibitors toward DNA methyltransferase and histone deacetylase activities resulted in the enhancement of biosynthetic pathway expression for new secondary metabolite production. Highlighting the biosynthesis of these metabolites in this review could draw the attention of molecular biologists and genetics-interested researchers for isolating genes accountable for the biosynthesis of these interesting metabolites; this could allow for the discovery of the detailed mechanisms of their formation by various enzymes, which could allow for the preparation these metabolites and their analogs by engineering their biosynthetic pathways.

**Author Contributions:** Conceptualization, S.R.M.I. and G.A.M.; resources, M.T.K., K.A.M. and A.M.O.; discussion of the contents, A.M.O., G.A.M. and S.R.M.I.; writing—original draft, M.T.K., K.A.M., A.M.O., G.A.M. and S.R.M.I.; writing—review and editing, G.A.M. and S.R.M.I. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research work was funded by Institutional Fund Projects under grant no. (IFPDP-254- 22). Therefore, the authors gratefully acknowledge technical and financial support from Ministry of Education and Deanship of Scientific Research (DSR), King Abdulaziz University (KAU), Jeddah, Saudi Arabia.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** This research work was funded by Institutional Fund Projects under grant no. (IFPDP-254-22). Therefore, the authors gratefully acknowledge technical and financial support from Ministry of Education and Deanship of Scientific Research (DSR), King Abdulaziz University (KAU), Jeddah, Saudi Arabia.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **Abbreviations**

