Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity.

New antibiotics with either a novel mode of action or novel mode of inhibition 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 IC50 = 2.0) and lower Mtb minimum inhibitor concentrations (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 structure-activity relationship expansion.

1,3-Diarylpyrazolyl-acylsulfonamides as Potent Anti-tuberculosis Agents Targeting Cell Wall Biosynthesis in Mycobacterium tuberculosis.

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.

Lerisetron Analogues with Antimalarial Properties: Synthesis, Structure-Activity Relationship Studies, and Biological Assessment.

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.

Expedient Access to Unsymmetrical Diarylindolylmethanes through Palladium-Catalyzed Domino Electrophilic Cyclization-Extended Conjugate Addition Approach.

A palladium-catalyzed domino process to access unsymmetrical diarylindolylmethanes has been developed through the annulation of o-alkynylanilines followed by 1,6-conjugate addition with p-quinone methides (p-QMs) under relatively mild conditions. The broad substrate scope of this methodology was demonstrated through the use of a wide range of substituted o-alkynylanilines and p-quinone methides, and in most cases, the unsymmetrical diarylindolylmethanes could be prepared in moderate to excellent yields. Notably, this method does not require any amino group protection. Moreover, 100% atom economy makes this transformation attractive from a green chemistry perspective.

A room-temperature protocol to access isoquinolines through Ag(I) catalysed annulation of o-(1-alkynyl)arylaldehydes and ketones with NH4OAc: elaboration to berberine and palmatine.

An efficient and mild protocol for the direct construction of aryl- and alkyl-substituted isoquinolines has been realized through silver nitrate catalyzed aromatic annulation of o-(1-alkynyl)arylaldehydes and ketones with ammonium acetate. The salient feature of this methodology is that this annulation could be effected at room temperature leading to a wide range of isoquinoline derivatives in good to excellent yields. Additionally, this approach has been employed to the synthesis of biologically important isoquinoline alkaloids such as berberine and palmatine.

Combining oxidative N-heterocyclic carbene catalysis with click chemistry: a facile one-pot approach to 1,2,3-triazole derivatives.

A combination of the oxidative N-heterocyclic carbene catalysis and click chemistry has been explored for the direct, one-pot synthesis of 1,2,3-triazole derivatives from aromatic aldehydes. This procedure was found to be very efficient and a variety of 1,2,3-triazole derivatives could be accessed through their corresponding propargyl esters in moderate-to-good yields under mild conditions.

N-heterocyclic carbene catalysed aerobic oxidation of aromatic aldehydes to aryl esters using boronic acids.

The organocatalytic behavior of N-heterocyclic carbenes in the aerobic oxidation of aromatic aldehydes to esters with boronic acids has been explored. This transition metal-free protocol allows access to a wide variety of aromatic esters in good to excellent yields under mild reaction conditions.