Design, Synthesis and Discovery of N,N’‐Carbazoyl‐aryl‐urea Inhibitors of Zika NS5 Methyltransferase and Virus Replication

Abstract

The recent outbreaks of Zika virus (ZIKV) infection worldwide make the discovery of novel antivirals against flaviviruses a research priority. This work describes the identification of novel inhibitors of ZIKV through a structure‐based virtual screening approach using the ZIKV NS5‐MTase. A novel series of molecules with a carbazoyl‐aryl‐urea structure has been discovered and a library of analogues has been synthesized. The new compounds inhibit ZIKV MTase with IC50 between 23–48 μM. In addition, carbazoyl‐aryl‐ureas also proved to inhibit ZIKV replication activity at micromolar concentration.

Chemoinformatic Design and Profiling of Derivatives of Dasabuvir, Efavirenz, and Tipranavir as Potential Inhibitors of Zika Virus RNA-Dependent RNA Polymerase and Methyltransferase

“…Previous studies have reported inhibitors of the zika virus replication/NS5-RNA-dependent RNA polymerase and/or NS5-methyltransferase ,,− ,,, using various strategies. This study identified some derivatives of the said parent compounds as potential inhibitors of the virus NS5 protein, and a previous report had validated N -[4-[6- tert -butyl-5-methoxy-8-(6-methoxy-2-oxo-1 H -pyridin-3-yl)-3 quinolyl] phenyl] methanesulfonamide (PubChem identifier: CID 49835560), a derivative of dasabuvir, against hepatitis C virus NS5B polymerase but not zika virus.…”

“…However, 1e showed equivalent binding energy of −6.675 ± 0.05 kcal/mol and K i of 12.67519392 ± 1.115312 μM for RNA-dependent RNA polymerase, while 4e showed equivalent binding energy of −7.6 ± 0.00 kcal/mol and K i of 2.648363028 ± 0.000000 μM for NS5-methyltransferase when compared with efavirenz, 3e, (−6.60 ± 0.00 kcal/mol and 14.34816176 ± 0.000000 μM for RNA-dependent RNA polymerase; −7.43 ± 0.05 kcal/mol and 3.568824547 ± 0.288630 μM for NS5-methyltransferase) (Supporting Information 1). Previous studies have reported inhibitors of the zika virus replication/NS5-RNA-dependent RNA polymerase and/or NS5-methyltransferase 2,13,[15][16][17][18][19]36,47,48 using various strategies. This study identified some derivatives of the said parent compounds as potential inhibitors of the virus NS5 protein, and a previous report had validated N- [4-[6-tert-butyl-5methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3 quinolyl] phenyl] methanesulfonamide (PubChem identifier: CID 49835560), a derivative of dasabuvir, against hepatitis C virus NS5B polymerase 44 but not zika virus.…”

“…The controversies, especially the controversial tissue research, could hamper essential research on ZIKV, like probing the link between the virus and birth defects including drug discovery. There are reported inhibitors of the zika virus replication/protein synthesis machinery including amodiaquine, hydroxychloroquine, dasabuvir, efavirenz, and tipranavir, ,− but no approved effective antiviral therapy (drugs or vaccines) directed against the virus for treatment (or prevention) is currently available. ,, Therefore, the discovery of novel antivirals against ZIKV is a research priority. To address this urgent medical need, we designed and profiled derivatives of dasabuvir, efavirenz, and tipranavir as potential inhibitors of the zika virus NS5 protein (RNA-dependent RNA polymerase (RdRP) and methyltransferase (MTase)).…”

Bixinoids Derived from Bixa orellana as a Potential Zika Virus Inhibitor Using Molecular Simulations. Antiviral Effect on the Zika Virus of Bixinoids

“…ZIKV NS5 methyltransferase is an important target in screening for new molecules that have an inhibitory effect on the action of this enzyme, as reported in previous studies who identified the molecules ZINC1652386 [55], and N, N'-Carbazoyl-aryl-urea [56], both as target molecules for the development of anti-ZIKV drugs. In rational drug planning, the "rule of five" (ROF) by Lipinski and coauthors [29] is often used to delimit the space of compounds with the greatest number of conditions satisfied to be an oral drug.…”

The Fellowship of Privileged Scaffolds—One Structure to Inhibit Them All

“…In 2019, Caruso et al published a review article about carbazole derivatives with antiviral activity [118]. Just to supplement this excellent review, at the end of 2019, Spizzichino et al presented a series of novel molecules based on a carbazoyl-aryl-urea structure which were potent Zika virus NS5 methyltransferase able to suppress virus replication [119]. SAR studies led to the creation of compound 74 as the most active inhibitor of ZIKV-NS5MTase with IC 50 = 23 µM in an enzyme-based assay.…”