ACS Medicinal Chemistry Letters最新文献

A library of 66 small molecules targeting IRE1α were designed using a molecular docking approach and prepared by a two-step reaction sequence using diverse substrates. All compounds utilized a 1-amino-4-bromonaphthalene core that was modified via Suzuki coupling with boronic acids to form intermediates that were carbamoylated to form urea-linked inhibitor candidates. We developed a 3³ DoE approach for the Suzuki coupling reaction that was optimized with 216 reactions via HTE. By screening the purified compounds in a tunicamycin-induced ER stress assay with ARPE-19 cells and quantifying their kinase inhibition activity by RT-qPCR, we identified 14 derivatives with the potential for IRE1α inhibition. IC₅₀ assays showed that six of the compounds displayed IRE1α inhibition alike KIRA6, a standard in IRE1α inhibition, with three of the leads possessing improved IC₅₀. Viability screens indicated that the best IRE1α inhibitors were not cytotoxic in the working concentrations and displayed improved protection from apoptosis compared to KIRA6.

Provided herein are novel compounds as TREM2 agonists, pharmaceutical compositions, use of such compounds in treating Alzheimer’s disease, and processes for preparing such compounds.

Pain management costs the world billions of dollars each year, and there are limited nonopioid options to treat people suffering from chronic pain. Opioids are excellent analgesics but are liable to abuse and fatal overdoses. This Microperspective summarizes challenges and opportunities pertaining to creating nonopioid drugs that could be used to treat chronic pain, substance abuse, fatty liver, or obesity by targeting the cannabinoid receptor type 1 (CB1).

Provided herein are novel cyanotriazole compounds, pharmaceutical compositions, use of such compounds in treating Chagas disease, leishmaniasis and human African trypanosomiasis (HAT), and processes for preparing such compounds.

Chikungunya virus (CHIKV) results in debilitating chronic pain in nearly half of those infected. With no FDA approved small molecule-based therapeutics available, we screened compounds to reveal quinazolinone (S)-1a with a modest 0.3 log reduction of CHIKV titer and no significant toxicity (CC₅₀ > 40 μM). Five scaffold regions were surveyed to improve the titer reduction efficiency. Chemistry was established to preserve the enantiopurity of 2-piperidinyl-containing analogues, affording (R)-1h (BDGR-651) which reduced CHIKV titer in normal human dermal fibroblasts by 4.1 log at 10 μM (EC₅₀ = 0.86 μM). Excellent solubility and mouse microsomal and plasma stabilities were observed, and confocal microscopy of infected Vero E6 cells treated with (R)-1h showed a dose-dependent protective effect. A narrow selectivity index prevented in vivo evaluation, but the study showed that antiencephalitic alphavirus quinazolinones could be reengineered to inhibit CHIKV, an arthritogenic virus, against which previous analogues showed no significant activity.

Provided herein are novel psilocin derivatives as serotonergic psychedelic agents, pharmaceutical compositions, use of such compounds in treating central nervous system (CNS) disorders, and processes for preparing such compounds.

RNA viruses such as SARS-CoV-2 and dengue virus pose global health threats, highlighting the urgent need for broad-spectrum antivirals with improved safety. We synthesized 8-aza Fluoroneplanocin derivatives designed to reduce cytotoxicity while maintaining antiviral potency. Among them, compound 3a, bearing an 8-aza adenine base, exhibited its potential broad-spectrum activity against SARS-CoV-2 (EC₅₀ = 12.2 μM) and dengue virus (E₅₀ = 37.4 μM), with no detectable cytotoxicity (CC₅₀ > 100 μM). Mechanistic studies showed that 3a moderately inhibited S-adenosylhomocysteine (SAH) hydrolase (IC₅₀ = 1.51 μM), in contrast to the potent inhibition by Fluoroneplanocin A (1, IC₅₀ = 0.15 μM), indicating that weaker SAH hydrolase inhibition contributes to reduced toxicity. Docking against SARS-CoV-2 RdRp revealed that 3a formed an additional hydrogen bond with Arg555, supporting RdRp binding as a complementary mechanism. Collectively, these results demonstrate the dual-targeting potential of 8-aza Fluoroneplanocins, offering a promising scaffold for the development of safe and effective broad-spectrum nucleoside antivirals.

Provided herein are novel bicyclic compounds as TLR7 agonists, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

Provided herein are novel azepinoindole compounds as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating neuropsychiatric and neurodegenerative disorders, and processes for preparing such compounds.