Chemistry and pharmacology of naamine and naamidine-type marine alkaloids: an update

The marine alkaloids naamine A and naamidine A were first isolated from a calcareous sponge forty years ago. Since 1987, about 40 related natural products have been discovered in this series, including naamines A-G, isonaamines A-D, naamidines A-K, isonaamidines A-E, pyronaamidine, spironaamidine, and a few other derivatives. The family also includes related imidazole alkaloids such as leucettamines, clathridines, calcaridines, as well as metal-coordinated dimeric products (e.g. (naamidine A) 2 -Zn and (naamidine J) 2 -Cu). Altogether, they represent a group of ∼ 70 imidazole alkaloids all isolated from marine species. Efficient and versatile synthetic processes have been set up to access these products and to design structural analogues. At the pharmacological level, studies have revealed the interest of these products to combat fungal and viral infections, and to treat certain cancers. A complete overview of these imidazole alkaloids, their chemistry, pharmacological properties and mechanisms of action is presented here. In several cases, key molecular targets have been identified, thus facilitating the structure-guided design of analogues and the identification of more potent synthetic analogues. Encouraging data have been reported with a naamidine A-based cream to treat mycosis, and with naamine A derivatives to viral (TMV) infections. In the naamidine J series, potent anticancer derivatives targeting key molecular targets (CSE1L, FDX1, PD-L1) have been characterized. Altogether, the analysis shed light on this family of marine alkaloids of prime medicinal interest, with the objectives to encourage further researches into their mechanism of action and bioactivities. • Naamines and naamidines are imidazole alkaloids essentially produced by marine sponges. • Over 60 alkaloids have been isolated, including several metal-complexed dimeric products. • Synthetic processes have been defined for access to the natural products and derivatives. • Lead products include naamidine A and J acting as antifungal and antiviral agents, respectively. • Synthetic derivatives with marked immune-regulatory and anticancer properties have been discovered.