Salicylamide derivatives for iron and aluminium sequestration. From synthesis to complexation studies

Development of N-(1-Adamantyl)benzamides as Novel Anti-Inflammatory Multitarget Agents Acting as Dual Modulators of the Cannabinoid CB2 Receptor and Fatty Acid Amide Hydrolase

“…The increase in the CB2R affinity exerted by the methoxy group, in particular in 2-position, encouraged to explore other alkyl groups. In agreement with Lucchesi et al, 24 benzylation of the hydroxyl function in 2-position leads to a striking recovery of the CB2R affinity (13, K i = 14.8 nM) compared to the phenol counterpart (17), and a 26-fold increase compared to the methoxy counterpart (25). A partial recovery of the CB2R affinity is recorded also with the 3-benzyloxy derivative 14 (K i = 313 nM), but no substantial improvement compared to the methoxy counterpart (10) is brought.…”

“…Thus, the 2-hydroxyl group has been alkylated with a n-pentyl chain (26) and a cyclohexylmethyl group (27), both resulting in nanomolar affinity (K i = 10.8 and 20.1 nM, respectively), in line with the corresponding benzyloxy analogue 13. All these 2-alkoxy groups, bigger than methoxy (25), confer a certain degree of CB1R affinity, mainly in a three-digit nanomolar range, except for 27 that displays the highest CB1R affinity of the series (K i = 67.6 nM). The presence of the 3-methoxy group was also studied in the 2-benzyloxy analogue 13 (i.e., the compound with the best compromise in terms of CB2R affinity and selectivity vs the CB1R).…”

“…Salicylamides, as well as benzamides, are able to chelate metals such as iron species and may thus be useful as scavengers of toxic metal ions . Accordingly, we evaluated the ability of the amides herein reported to chelate iron­(II) through the “Ferrozine assay”, that is, the colorimetric assay used for the quantitation of iron­(II) in cultured cells …”

“…Considering the reported activity of salicylamides, as well as benzamides, as iron species chelating agents and the potential use of these ligands in a neuroprotective approach, all the derivatives were also tested for their ability to chelate iron ion species to further clarify their therapeutic potential. , These findings allow us to suggest these ligands as first-in-class for the development of multitarget agents able to alleviate or prevent the inflammatory cascade that is the leading detrimental step in several severe diseases such as neurodegeneration, cancer, and COVID-19. The ability of the best compounds to permeate the blood–brain barrier (BBB) was also predicted and experimentally tested (see the Supporting Information, “ P -glycoprotein interaction” section and Figure S1), demonstrating their capability to access the CNS.…”

Metal self-assembly mimosine peptides with enhanced antimicrobial activity: towards a new generation of multitasking chelating agents

“…The dissociated hydroxyl group is coordinating the iron ion, whereas both N-end and C-end (amide protected) of the peptide remain protonated, at pH 1.0. Compared to amines, amides are weaker bases, and therefore do not present noticeable acidbase properties in water; 61 they are protonated only at a low pH (<4). In the solution of the metal and peptide at a 1 : 3 molar ratio, at pH 4.0, two additional bands appear, with maximum values at 491 and 457 nm; these bands can be attributed to the [Fe(P1) 2 H 2 ] 3+ and [Fe(P1) 3 H 3 ] 3+ complexes, respectively.…”