Azolylpyrimidinediols as Novel Structural Scaffolds of DNA-Groove Binders against Intractable Acinetobacter baumannii

A unique class of antibacterial azolylpyrimidinediols
(APDs) and
their analogues were developed. Some synthesized compounds showed
excellent bacteriostatic potency; especially, triazolylpyrimidinediol
(triazolyl PD) 7a exhibited good anti-Acinetobacter baumannii potential with a low MIC
of 0.002 mmol/L. Triazolyl PD 7a with inconspicuous cytotoxicity
and hemolytic activity could eradicate the established biofilm, showed
low resistance, and exhibited favorable drug-likeness. Mechanistic
explorations revealed that compound 7a without membrane-targeting
ability could decrease metabolic activity, interact with DNA through
groove binding action to block DNA replication rather than intercalate
into and cleave DNA, and thus inhibit bacterial growth. Further computations
displayed that the low EHOMO and large
energy gap might help triazolyl PD 7a binding to biological
targets more easily. Moreover, compound 7a gave appreciable in vivo pharmacokinetic properties and pharmacodynamics.
These findings of azolylpyrimidinediols as novel structural scaffolds
of DNA-groove binders might imply a large promise for the treatments
of Acinetobacter baumannii infection.