N-PHOSPHORYLATION OF AMINOTHIAZOLES AND AMINO-THIADIAZOLES WITH P(III)- AND P(V)-REAGENTS: SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY

Abstract

This study investigates the N-phosphorylation of key mono- and diaminoheterocycles within the thiazole and thiadiazole series using dimethyl chlorophosphate (P(V)) and 1-tert-butoxy-N,N,N',N'-tetraethylphosphanediamine (P(III)) reagents. Eight novel derivatives were successfully synthesized and isolated. Reaction conditions were optimized, employing triethylamine in acetonitrile at 80 °C for P(V) agents, and ethyl acetate at 80 °C via diethylamine elimination for P(III) agents. Diamino substrates underwent efficient, symmetric bis-phosphorylation at both exocyclic amino positions. Due to the electron-withdrawing effect of the second endocyclic nitrogen in the thiadiazole core, its amino groups showed lower nucleophilicity, resulting in lower yields (31–41%) compared to thiazole counterparts (65–83%). Structural frameworks were confirmed by 31P NMR spectroscopy, appearing at δ 5.85–5.92 ppm for phosphoramidates and δ 124.66–128.48 ppm for phosphoramidites. In vitro screening demonstrated a strong, dose-dependent antimicrobial profile, with Gram-negative strains displaying enhanced susceptibility. Trivalent phosphorus derivative emerged as the most potent broad-spectrum candidate. Against P. aeruginosa, 1-tert-butoxy-N,N-diethyl-N'-(1,3,4-thiadiazol-2-yl)phosphanediamine exhibited a 27–33 mm inhibition zone, outperforming streptomycin (MIC = 6.25, MBC = 12.5 µg/ mL). Against T. viride, it outclassed clotrimazole with a 30–39 mm zone (MIC = 12.5, MFC = 25 µg/mL). The results obtained open up broad prospects for the development of new, highly effective antibacterial and antifungal agents based on phosphorylated heterocycles.