New antibiotics with either a novel mode-of-action (MoA) or novel mode-of-inhibition (MoI) are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitors having activity against drug resistant Mycobacterium tuberculosis (Mtb), the causative agent of TB. While the clinical candidate zoliflodacin has progressed to Phase 3 trials for the treatment of gonorrhea, compounds herein demonstrated higher inhibitory potency against Mtb DNA gyrase (e.g., Compound 42 with an IC50 = 2.0) and lower Mtb MICs (0.49 µM for 42). Notably, 42 and analogues showed selective Mtb activity relative to representative Gram-positive and Gram-negative bacteria. DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA while on-target activity was supported by hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs with Mtb DNA gyrase was developed and a structural hypothesis was built for SAR expansion.
Phenotypic
whole cell high-throughput screening of a ∼150,000
diverse set of compounds against Mycobacterium tuberculosis (Mtb) in cholesterol-containing media identified 1,3-diarylpyrazolyl-acylsulfonamide 1 as a moderately active hit. Structure–activity relationship
(SAR) studies demonstrated a clear scope to improve whole cell potency
to MIC values of <0.5 μM, and a plausible pharmacophore model
was developed to describe the chemical space of active compounds.
Compounds are bactericidal in vitro against replicating
Mtb and retained activity against multidrug-resistant clinical isolates.
Initial biology triage assays indicated cell wall biosynthesis as
a plausible mode-of-action for the series. However, no cross-resistance
with known cell wall targets such as MmpL3, DprE1, InhA, and EthA
was detected, suggesting a potentially novel mode-of-action or inhibition.
The in vitro and in vivo drug metabolism
and pharmacokinetics profiles of several active compounds from the
series were established leading to the identification of a compound
for in vivo efficacy proof-of-concept studies.
A phenotypic whole cell high-throughput
screen against the asexual
blood and liver stages of the malaria parasite identified a benzimidazole
chemical series. Among the hits were the antiemetic benzimidazole
drug Lerisetron 1 (IC50 NF54 = 0.81 μM)
and its methyl-substituted analogue 2 (IC50 NF54 = 0.098 μM). A medicinal chemistry hit to lead effort
led to the identification of chloro-substituted analogue 3 with high potency against the drug-sensitive NF54 (IC50 NF54 = 0.062 μM) and multidrug-resistant K1 (IC50 K1 = 0.054 μM) strains of the human malaria parasite Plasmodium falciparum. Compounds 2 and 3 gratifyingly showed in vivo efficacy in both Plasmodium berghei and P. falciparum mouse models of malaria. Cardiotoxicity risk as expressed in strong
inhibition of the human ether-a-go-go-related gene (hERG) potassium
channel was identified as a major liability to address. This led to
the synthesis and biological assessment of around 60 analogues from
which several compounds with improved antiplasmodial potency, relative
to the lead compound 3, were identified.
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