Inhibitors of Dengue virus and West Nile virus proteases based on the aminobenzamide scaffold.
Dengue and West Nile viruses (WNV) are mosquito-borne members of flaviviruses that cause significant morbidity and mortality. There is no approved vaccine or antiviral drugs for human use to date. In this study, a series of functionalized meta and para aminobenzamide derivatives were synthesized and subsequently screened in vitro against Dengue virus and West Nile virus proteases. Four active compounds were identified which showed comparable activity toward the two proteases and shared in common a meta or para(phenoxy)phenyl group. The inhibition constants (K(i)) for the most potent compound 7n against Dengue and West Nile virus proteases were 8.77 and 5.55 μM, respectively. The kinetics data support a competitive mode of inhibition of both proteases by compound 7n. This conclusion is further supported by molecular modeling. This study reveals a new chemical scaffold which is amenable to further optimization to yield potent inhibitors of the viral proteases via the combined utilization of iterative medicinal chemistry/structure-activity relationship studies and in vitro screening.
Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
Sridhar
S
Aravapalli
Huiguo
H
Lai
Tadahisa
T
Teramoto
Kevin R
KR
Alliston
Gerald H
GH
Lushington
Eron L
EL
Ferguson
R
R
Padmanabhan
William C
WC
Groutas
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D003716:Dengue Virus / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014902:West Nile virus / Q000187:drug effects / Q000201:enzymology*
D000998:Antiviral Agents; D001549:Benzamides; D010671:Phenylurea Compounds; D011480:Protease Inhibitors; D014230:Triazoles; C037689:benzamide; D010447:Peptide Hydrolases