78940-65-5Relevant academic research and scientific papers
Salicylanilides Reduce SARS-CoV-2 Replication and Suppress Induction of Inflammatory Cytokines in a Rodent Model
Beutler, Nathan,Blake, Steven,Eubanks, Lisa M.,Janda, Kim D.,Ji, Henry,Manning, John T.,Maruyama, Junki,Paessler, Slobodan,Shaabani, Namir,Teijaro, John R.
, p. 2229 - 2237 (2021/08/24)
SARS-CoV-2 virus has recently given rise to the current COVID-19 pandemic where infected individuals can range from being asymptomatic, yet highly contagious, to dying from acute respiratory distress syndrome. Although the world has mobilized to create antiviral vaccines and therapeutics to combat the scourge, their long-term efficacy remains in question especially with the emergence of new variants. In this work, we exploit a class of compounds that has previously shown success against various viruses. A salicylanilide library was first screened in a SARS-CoV-2 activity assay in Vero cells. The most efficacious derivative was further evaluated in a prophylactic mouse model of SARS-CoV-2 infection unveiling a salicylanilide that can reduce viral loads, modulate key cytokines, and mitigate severe weight loss involved in COVID-19 infections. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and a previously established favorable pharmacokinetic profile for the lead salicylanilide renders salicylanilides in general as promising therapeutics for COVID-19.
Salicylanilide Analog Minimizes Relapse of Clostridioides difficile Infection in Mice
Blake, Steven,Thanissery, Rajani,Rivera, Alissa J.,Hixon, Mark S.,Lin, Mingliang,Theriot, Casey M.,Janda, Kim D.
, p. 6898 - 6908 (2020/07/28)
Clostridioides difficile infection (CDI) causes serious and sometimes fatal symptoms like diarrhea and pseudomembranous colitis. Although antibiotics for CDI exist, they are either expensive or cause recurrence of the infection due to their altering the colonic microbiota, which is necessary to suppress the infection. Here, we leverage a class of known membrane-targeting compounds that we previously showed to have broad inhibitory activity across multiple Clostridioides difficile strains while preserving the microbiome to develop an efficacious agent. A new series of salicylanilides was synthesized, and the most potent analog was selected through an in vitro inhibitory assay to evaluate its pharmacokinetic parameters and potency in a CDI mouse model. The results revealed reduced recurrence of CDI and diminished disturbance of the microbiota in mice compared to standard-of-care vancomycin, thus paving the way for novel therapy that can potentially target the cell membrane of C. difficile to minimize relapse in the recovering patient.
Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2
Liu, Qiufeng,Huang, Fubao,Yuan, Xiaojing,Wang, Kai,Zou, Yi,Shen, Jianhua,Xu, Yechun
supporting information, p. 10231 - 10244 (2018/01/10)
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.
Synthesis and anti-CVB 3 evaluation of substituted 5-nitro-2-phenoxybenzonitriles
Puerstinger, Gerhard,De Palma, Armando M.,Zimmerhofer, Guenther,Huber, Simone,Ladurner, Sophie,Neyts, Johan
experimental part, p. 5123 - 5125 (2009/04/16)
The synthesis and SAR of a series of 60 substituted 2-phenoxy-5-nitrobenzonitriles (analogues of MDL-860) as inhibitors of enterovirus replication (in particular of coxsackievirus B3 (CVB 3)) are reported. Several of the analogues inhibited CVB 3 and othe
Substituted benzonitriles having antiviral activity
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, (2008/06/13)
Substituted benzonitriles having antiviral activity are disclosed. Methods of use based on the antiviral activity of the compounds are also disclosed, as well as compositions which comprise a carrier in combination with a suitable antiviral active compoun
