Phosphorus-nitrogen compounds. Part 78. Design, synthesis, crystallographic and spectral properties, free radical scavenging and bioactivity studies of tetrakis(alkylamino)monoferrocenyl-(N/N)-spiro-cyclotriphosphazenes

Abstract Herein, new hybrid inorganic/organic heterocyclic cyclotriphosphazenes were synthesized to investigate their spectral/crystallographic properties and bioactivity. For this purpose, ferrocenyl units containing diamines with proven biological activity and primary amino groups were incorporated on the basis of robust trimeric phosphazene ring, a biocompatible material. Tetrachloromonoferrocenyl–(N/N)–spirocyclotriphosphazenes ( 1 – 3 ) were synthesized from the reactions of hexachlorocyclotriphosphazene, N 3 P 3 Cl 6 ( HCCP ), with ferrocenyldiamines. Nucleophilic substitution reactions of tetrachloro-phosphazenes ( 1–3 ) with n -propyl and n -butyl amines gave tetrakis( n -propylamino) ( 1a , 2a , and 3a ) and tetrakis( n -butylamino) ( 1b , 2b , and 3b ) monoferrocenyl–(N/N)–spirocyclotriphosphazenes, respectively. Elemental analysis, FTIR, 1 H, 13 C, 31 P NMR, HSQC and QTOF-MS methods were used for the characterization of these phosphazenes. Structural evaluations proved that fully ( n -alkylamino)cyclotriphosphazenes were obtained by nucleophilic substitution reactions. The crystal structure of tetrakis( n -butylamino)monoferrocenyl-(N/N)-spirocyclotriphosphazene ( 2b ) was elucidated crystallographically. The phosphazene ring is in flattened-boat conformation with a total puckering amplitude Q T of 0.2390. However, the cytotoxic, antimicrobial and antioxidant activities of the compounds and their interactions with DNA were also evaluated. All compounds were more potent than chloramphenicol against B. subtilis G(+) and (except for 1a ) had higher antifungal activity than ketoconazole against C. albicans . Tetrakis( n -butylamino)monoferrocenyl-(N/N)-spirocyclotriphosphazenes had much superior activity against C. tropicalis considering their MIC values. In particular, 1b , 2b , 3a , and 3b exhibited remarkable antimicrobial properties positioning them as strong candidates to combat the increasing challenge of antimicrobial resistance. In addition, 2a was concluded to be a good anticancer agent based on in vitro cytotoxic activity studies.