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

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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, N3P3Cl6 (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, 1H, 13C, 31P 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.