176690-89-4Relevant articles and documents
Design, synthesis and evaluation against Chikungunya virus of novel small-molecule antiviral agents
Tardugno, Roberta,Giancotti, Gilda,De Burghgraeve, Tine,Delang, Leen,Neyts, Johan,Leyssen, Pieter,Brancale, Andrea,Bassetto, Marcella
, p. 869 - 874 (2018/01/18)
Chikungunya virus is a re-emerging arbovirus transmitted to humans by mosquitoes, responsible for an acute flu-like illness associated with debilitating arthralgia, which can persist for several months or become chronic. In recent years, this viral infection has spread worldwide with a previously unknown virulence. To date, no specific antivirals treatments nor vaccines are available against this important pathogen. Starting from the structures of two antiviral hits previously identified in our research group with in silico techniques, this work describes the design and preparation of 31 novel structural analogues, with which different pharmacophoric features of the two hits have been explored and correlated with the inhibition of Chikungunya virus replication in cells. Structure-activity relationships were elucidated for the original scaffolds, and different novel antiviral compounds with EC50 values in the low micromolar range were identified. This work provides the foundation for further investigation of these promising novel structures as antiviral agents against Chikungunya virus.
Identification and Structure-Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli
Haynes, Keith M.,Abdali, Narges,Jhawar, Varsha,Zgurskaya, Helen I.,Parks, Jerry M.,Green, Adam T.,Baudry, Jerome,Rybenkov, Valentin V.,Smith, Jeremy C.,Walker, John K.
, p. 6205 - 6219 (2017/08/02)
In Gram-negative bacteria, efflux pumps are able to prevent effective cellular concentrations from being achieved for a number of antibiotics. Small molecule adjuvants that act as efflux pump inhibitors (EPIs) have the potential to reinvigorate existing antibiotics that are currently ineffective due to efflux mechanisms. Through a combination of rigorous experimental screening and in silico virtual screening, we recently identified novel classes of EPIs that interact with the membrane fusion protein AcrA, a critical component of the AcrAB-TolC efflux pump in Escherichia coli. Herein, we present initial optimization efforts and structure-activity relationships around one of those previously described hits, NSC 60339 (1). From these efforts we identified two compounds, SLUPP-225 (17h) and SLUPP-417 (17o), which demonstrate favorable properties as potential EPIs in E. coli cells including the ability to penetrate the outer membrane, improved inhibition of efflux relative to 1, and potentiation of the activity of novobiocin and erythromycin.
Benzo[d]imidazole transient receptor potential vanilloid 1 antagonists for the treatment of pain: Discovery of trans-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Mavatrep)
Parsons, William H.,Calvo, Raul R.,Cheung, Wing,Lee, Yu-Kai,Patel, Sharmila,Liu, Jian,Youngman, Mark A.,Dax, Scott L.,Stone, Dennis,Qin, Ning,Hutchinson, Tasha,Lubin, Mary Lou,Zhang, Sui-Po,Finley, Michael,Liu, Yi,Brandt, Michael R.,Flores, Christopher M.,Player, Mark R.
, p. 3859 - 3874 (2015/05/27)
Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 4 antagonized capsaicin-induced Ca2+ influx, with an IC50 value of 4.6 nM. In the complete Freund's adjuvant- and carrageenan-induced thermal hypersensitivity models, 4 exhibited full efficacy, with ED80 values of 7.8 and 0.5 mg/kg, respectively, corresponding to plasma levels of 270.8 and 9.2 ng/mL, respectively. On the basis of its superior pharmacologic and safety profile, 4 (mavatrep) was selected for clinical development for the treatment of pain.
