Molecular iodine catalyzed oxidative coupling of 2-aminobenzamides with aryl methyl ketones produced 2-aryl quinazolin-4(3H)-ones. The reaction performed well in the absence of any metal or ligand. The quantity of iodine played a very crucial role in this transformation in order to selectively get 2-aryl quinazolin-4(3H)-ones. The utility of this protocol for synthesis of pyrazolo[4,3-d]pyrimidin-7(6H)-ones including a key intermediate involved in sildenafil synthesis has also been demonstrated.
NLRP3 inflammasome is an important therapeutic target for a number of human diseases. Herein, computationally designed series of quinazolin-4(3H)-ones were synthesized using iodine-catalyzed coupling of arylalkynes (or styrenes) with O-aminobenzamides. The key event in this transformation involves the oxidative cleavage of the C−C triple/ double bond and the release of formaldehyde. The reaction relies on the C−N bond formation along with the C−C bond cleavage under metal-free conditions. The nitro-substituted quinazolin-4(3H)-one 2k inhibited NLRP3 inflammasome (IC 50 5 μM) via the suppression of IL-1β release from ATP-stimulated J774A.1 cells.
A new simple and efficient metal-free 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) promoted regioselective synthesis of 3,5-disubstituted isoxazoles and isoxazolines from aldoximes has been described. This method allows reaction to proceed efficiently on aldoximes containing 10 unprotected phenolic hydroxyl group. Furthermore, with the use of higher equivalents of N-chlorosuccinimide, chlorosubstituted isoxazoles and isoxazolines were obtained as the only products via tandem one-pot 1,3-dipolar cycloaddition followed by regioselective chlorination. 15
Activation of prostanoid
EP2 receptor exacerbates neuroinflammatory
and neurodegenerative pathology in central nervous system diseases
such as epilepsy, Alzheimer’s disease, and cerebral aneurysms.
A selective and brain-permeable EP2 antagonist will be useful to attenuate
the inflammatory consequences of EP2 activation and to reduce the
severity of these chronic diseases. We recently developed a brain-permeable
EP2 antagonist 1 (TG6-10-1), which displayed anti-inflammatory
and neuroprotective actions in rodent models of status epilepticus.
However, this compound exhibited moderate selectivity to EP2, a short
plasma half-life in rodents (1.7 h) and low aqueous solubility (27
μM), limiting its use in animal models of chronic disease. With
lead-optimization studies, we have developed several novel EP2 antagonists
with improved water solubility, brain penetration, high EP2 potency,
and selectivity. These novel inhibitors suppress inflammatory gene
expression induced by EP2 receptor activation in a microglial cell
line, reinforcing the use of EP2 antagonists as anti-inflammatory
agents.
EP2, a G-protein-coupled prostaglandin-E 2 receptor, has emerged as a seminal biological target for drug discovery. EP2 receptor activation is typically proinflammatory; therefore, the development of EP2 antagonists to mitigate the severity and disease pathology in a variety of inflammation-driven central nervous system and peripheral disorders would be a novel strategy. We have recently developed a second-generation EP2 antagonist TG8-260 and shown that it reduces hippocampal neuroinflammation and gliosis after pilocarpine-induced status epilepticus in rats. Here, we present details of synthesis, lead optimization on earlier leads that resulted in TG8-260, potency and selectivity evaluations using cAMP-driven time-resolved fluorescence resonance energytransfer (TR-FRET) assays and [H 3 ]-PGE2-binding assays, absorption, distribution, metabolism, and excretion (ADME), and pharmacokinetics. TG8-260 (2f) showed Schild K B = 13.2 nM (3.6-fold more potent than the previous lead TG8-69 (1c)) and 500-fold selectivity to EP2 against other prostanoid receptors. Pharmacokinetic data indicated that TG8-260 has a plasma half-life of 2.14 h (PO) and excellent oral bioavailability (77.3%). Extensive ADME tests indicated that TG8-260 is a potent inhibitor of CYP450 enzymes. Further, we show that TG8-260 displays antagonistic activity on the induction of EP2 receptor-mediated inflammatory gene expression in microglia BV2-hEP2 cells; therefore, it can serve as a tool for investigating anti-inflammatory pathways in peripheral inflammatory disease animal models.
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