Azolylpyrimidinediols as Novel Structural Scaffolds of DNA-Groove Binders against Intractable <i>Acinetobacter baumannii</i>

Abstract

A unique class of antibacterial azolylpyrimidinediols (APDs) and their analogues were developed. Some synthesized compounds showed excellent bacteriostatic potency; especially, triazolylpyrimidinediol (triazolyl PD) <b>7a</b> exhibited good anti-<i>Acinetobacter baumannii</i> potential with a low MIC of 0.002 mmol/L. Triazolyl PD <b>7a</b> with inconspicuous cytotoxicity and hemolytic activity could eradicate the established biofilm, showed low resistance, and exhibited favorable drug-likeness. Mechanistic explorations revealed that compound <b>7a</b> 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 <i>E</i>_HOMO and large energy gap might help triazolyl PD <b>7a</b> binding to biological targets more easily. Moreover, compound <b>7a</b> gave appreciable <i>in vivo</i> 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 <i>Acinetobacter baumannii</i> infection.