A gram-scale synthesis of a macrocyclic amidinourea with strong antifungal activity through a Fukuyama tri-protected polyamine intermediate

Abstract

Systemic fungal infections are, nowadays, of crucial importance and, thus, in the last decade, we explored the great potential of natural and synthetic guanylated compounds, a great amount of work that led to the development of new non-azole antifungal compounds bearing a macrocycle, endowed with potent antifungal activity. We planned many biological assays to evaluate this class, implying always greater amount of compounds needed. This triggered us to setup a convenient strategy to prepare, in an easy and affordable way, grams of compound to be tested in excellent overall yield.

General Approach for the Liquid-Phase Fragment Synthesis of Orthogonally Protected Naturally Occurring Polyamines and Applications Thereof

“…The synthesis of PA analogues and conjugates has followed two traditional pathways. The first one involves the selective direct or indirect functionalization of the desired amino function(s) of a PA skeleton, and the second one, the assembly of the PA skeleton from readily available fragments bearing suitable functionalized or protected amino functionalities. ,,− We were recently interested in the selective monofunctionalization of the unsymmetrical Tsm, and we therefore decided to attempt the synthesis of orthogonally protected Tsm using the fragment synthesis protocol. It should be noted that monofunctionalization of the symmetrical PA Spm has been effected by using the N 1 , N 4 , N 8 -Boc 3 -Spm obtained via the low-temperature selective mono-trifluoroacetylation of Spm .…”

Discovery and Optimization of a Novel Macrocyclic Amidinourea Series Active as Acidic Mammalian Chitinase Inhibitors

“…As part of Prof. Maurizio Botta’s research on antimicrobials, a series of macrocyclic amidinoureas (MCAs) (representative compounds BM1 , BM21 , and BM24 are depicted in Figure ) were developed as potent antifungal agents, especially against Candida spp. with minimal inhibitory concentrations (MICs) ranging from 1 to 32 μg/mL. − Aimed at investigating their mode of action (MoA), we resorted to a computational target fishing approach that pointed attention toward fungal chitinases. Enzymatic assays on Trichoderma viride ( T. viride ) chitinase revealed a micromolar inhibition (inhibition constant ( K i ) ranging from 14.1 to 50.8 μM), confirming the in silico results .…”