Phosphorus–nitrogen compounds. Part 80. Design and synthesis of hybrid multiheterocyclic cyclotriphosphazene conjugates bearing unsymmetrical pendant arms: spectral and crystallographic characterization, bioactivity and structure–activity relationship (SAR) studies
Abstract
Hexachlorocyclotriphosphazene, N3P3CI6 (HCCP), serves as the main inorganic template to produce organocyclotriphosphazenes. Herein, initially, diamines (1–6) were synthesized, which were used as ligands to obtain tetrachlorospirocyclotriphosphazenes (1a–6a). Geminal dichloro (7–9) and fully substituted (10–13) N-ferrocenyl-N′-(4-chlorobenzyl)spiro-(NN)-cyclotriphosphazenes were obtained from the reactions of tetrachlorophosphazenes (5a and 6a) with pyrrolidine and 1,4-dioxa-8-aza-spiro [4,5]decane (DASD). Geminal phosphazenes (7–9) have “chiral P atoms”. The 31P-spectrum of 9 with the addition of chiral solvating agent (CSA), (R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol, proved that this compound exists as a “racemate.” The structural characterizations of the new phosphazenes were carried out using 1D NMR (1H, 13C, 31P) and LC-MS techniques. Single-crystal X-ray crystallography revealed the molecular and crystal structures of tetrachloro (5a and 6a) and tetra-pyrrolidino (10) cyclotriphosphazenes. Moreover, the highest free radical scavenging activities (FRSAs, %) were observed for 8 (21.8 ± 0.6). In addition, interactions with DNA and enzyme digestions were investigated. Also, the antibacterial and antifungal activities of all compounds were evaluated and compared with various cyclotriphosphazenes containing ferrocenyl/4-chlorobenzyl pendant arms for the structure–activity relationship (SAR) using MIC, MBC and MFC values. Dichlorophosphazene 8 (MIC = 9.8 μM) is very effective against B. cereus, B. subtilis, S. aureus, E. faecalis and E. hirae bacteria. However, fully-substituted phosphazene 10 (MIC = 9.8 μM) exhibits potent antifungal activity against C. albicans and C. krusei. These distinctions highlight their potential for specific bacterial and fungal threats.