Isosteres of hydroxypyridinethione as drug-like pharmacophores for metalloenzyme inhibition

Abstract

Hydroxypyridinethiones (HOPTOs) are strong ligands for metal ions and potentially useful pharmacophores for inhibiting metalloenzymes relevant to human disease. However, HOPTOs have been sparingly used in drug discovery efforts due, in part, to concerns that this scaffold will act as a promiscuous, non-selective metalloenzyme inhibitor, as well as possess poor pharmacokinetics (PK), which may undermine drug candidates containing this functional group. To advance HOPTOs as a useful pharmacophore for metalloenzyme inhibitors, a library of 22 HOPTO isostere compounds has been synthesized and investigated. This library demonstrates that it is possible to maintain the core metal-binding pharmacophore (MBP) while generating diversity in structure, electronics, and PK properties. This HOPTO library has been screened against a set of four different metalloenzymes, demonstrating that while the same metal-binding donor atoms are maintained, there is a wide range of activity between metalloenzyme targets. Overall, this work shows that HOPTO isosteres are useful MBPs and valuable scaffolds for metalloenzyme inhibitors.

Towards Identification of Essential Structural Elements of Organoruthenium(II)‐Pyrithionato Complexes for Anticancer Activity

“…[21] The same group proceeded to prepare 21 more pyrithione analogues and furthers tudied the structure-activity relationship of metalbinding pharmacophores. [22] With thesed ata in hand, we decided to preparea na rray of ten organoruthenium(II) chlorido (1a-e)a nd pta (2a-e)c omplexes ( Figure 2). After an in-depth study of their stabilities under biologically relevant conditions, all compoundsw ere screened for their cytotoxicities against seven cancerc ell lines and IC 50 values were determined.…”

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

“…Recent studies have begun to explore the effect of MBP isosteric replacement in metalloenzyme inhibition and pharmacokinetic profile. [41,42] In this study,w ereport the development and evaluationo f 10 DPAi sosteres ( Figure 2) as inhibitors of NDM-1 and related MBLs. As election of carboxylic acid isostere motifs was chosen to span ar ange of acidity (pK a )v alues and metal coordination preferences.V arying the identity of the isostere impacts both inhibition value andi nhibition mechanism.A dditionally,w e show the re-engineering of an isosteref rom am etal-stripping mechanism to one that favors the formation of at ernary complex.…”

“…[37][38][39] The ionizable nature of the carboxylic acid under physiological conditions (pH 7.4) makes it au seful handle for generating strong inhibitor-target interactions (i.e., electrostatic and hydrogen bonds). [41,42] In this study,w ereport the development and evaluationo f 10 DPAi sosteres ( Figure 2) as inhibitors of NDM-1 and related MBLs. [40] Despite the efficacy of this functional group, its usefulness can be limited in drug development due to poor cell permeability, metabolic instability,a nd off-target effects.…”

Alison Butler: papers in celebration of her 2018 ACS Alfred Bader Award in Bioorganic or Bioinorganic Chemistry

“…Five articles comprise the last section, on metallodrugs and metals in medical imaging. Cohen and co-authors [21] show that hydroxypyridinethione isosteric ligands are useful metal-binding pharmacophores and hence useful scaffolds for inhibitors of disease-associated metalloenzymes. Donnelly and co-authors [22] report on new radioactive technetium-99 m complexes for single-photon emission computed tomography (SPECT) imaging, which is useful for assisting in diagnosis of cerebral amyloid angiopathy.…”