Seeking heterocyclic scaffolds as antivirals against dengue virus

Abstract

Dengue is one of the most typical viral infection categorized in the Neglected Tropical Diseases (NTDs). It is transmitted via the female Aedes aegypti mosquito to humans and majorly puts risk to the lives of more than half of the world. Recent advancements in medicinal chemistry have led to the design and development of numerous potential heterocyclic scaffolds as antiviral drug candidates for the inhibition of the dengue virus (DENV). Thus, in this review, we have discussed the significance of inhibitory and antiviral activities of nitrogen, oxygen, and mixed (nitrogen-sulfur and nitrogen-oxygen) heterocyclic scaffolds that are published in the last seven years (2016-2022). Furthermore, we have also discussed the probable mechanisms of action and the diverse structure-activity relationships (SARs) of the heterocyclic scaffolds. In addition, this review has elaborately outlined the mechanism of viral infection and the life cycle of DENV in the host cells. The wide set of heterocycles and their SARs will aid in the development of pharmaceuticals that will allow the researchers to synthesize the promising anti-dengue drug candidate in the future.

Keywords: Antiviral medication; Dengue virus; Heterocyclic scaffolds; Neglected tropical diseases; Structure-activity relationship; Surface activity.

Graphical abstract

Fig. 1

Timeline showing the advancement of therapeutic compounds in the treatment of Dengue from 2015 to 2021.

Fig. 2

The detailed life cycle of DENV.

Fig. 3

Genomic arrangement of DENV.

Fig. 4

SAR of the triazole substituents responsible for showing anti-dengue activities.

Fig. 5

SAR of the 1,2,4-Triazole scaffolds reported by Vishvakarma et al. for the inhibition of ns2B-nsP3 protease.

Fig. 6

SAR of the p-substituents on the Ph-ring of the pyrazole substituents for the inhibition of DENV.

Fig. 7

SAR of the selected pyrazole-containing heterocyclic scaffolds showing maximum inhibition against the Huh-7 cell infected with DENV2.

Fig. 8

Positional isomers of the trisubstituted pyrazole scaffolds.

Fig. 9

SAR of the fluorinated-Pyrazoline scaffold showing inhibition against DENV2 serotype.

Fig. 10

SAR of the imidazole-based nucleoside scaffolds.

Fig. 11

Structure of the DMB220 molecule.

Fig. 12

SAR of the isothiazolo [4,3-b] pyridines for the inhibition of GAK and DENV.

Fig. 13

SAR of isothiazolo [4,3-b] pyridines.

Fig. 14

Examples of 3,5-disubstituted pyrrolo [2,3-b] pyridines inhibiting AAK1 and DENV.

Fig. 15

SAR of the substituted isothiazolo [4,3-b]pyridines for the GAK inhibition.

Fig. 16

SAR of the pyrazine-2,3-dicarboxamide substituted pyrazole scaffolds for the inhibition of DENV.

Fig. 17

SAR of disubstituted pyrimidine analogs against the DENV strains.

Fig. 18

SAR of the substituted pyrimidine scaffolds for the inhibition of DENV.

Fig. 19

Structure of the most potent inhibitory compound for the inhibition of RdRp DENV-2 serotype.

Fig. 20

SAR of the indole-derivatives showing inhibition against the larvae of Aedes aegypti mosquitoes.

Fig. 21

The most potent inhibitor of DENV2.

Fig. 22

SAR of the most potent tricyclic indoline and imidazolidone fused scaffolds showing inhibition against the DENV.

Fig. 23

SAR of the indole-containing scaffolds against DV2pro.

Fig. 24

SAR of the 4-anilinoquinoline analogs against the inhibition of DENV.

Fig. 25

Structures of aminoquinazoline-derivatives inhibiting DENV.

Fig. 26

SAR of the trimethoxy anilinoquinazoline scaffolds against the inhibition of DENV.

Fig. 27

SAR of the acetylene-substituted anilinoquinazoline scaffolds against the inhibition of DENV.

Fig. 28

Structure and SAR of two Coumarins derived from the seeds of Mammea americana.

Fig. 29

SAR of the N-substituted 1,2-benzoisothiazol-3(2H)-ones derivatives against the inhibition of DENV.

Fig. 30

SAR of the benzothiazole-based heterocyclic scaffolds against DENV2 NS2B/NS3 protease.

Fig. 31

SAR of the conjugated thiazolidinone-thiazole scaffolds against DENV-2 NS5 RdRp polymerase.

Fig. 32

SAR of the 2,1-benzothiazine 2,2-dioxide against DENV3 NS5 RdRp.

Fig. 33

SAR of the oxadiazole derivatives for the inhibition of DENV.

Fig. 34

SAR of the oxadiazole derivatives against the female Aedes aegypti mosquitoes.

Fig. 35

SAR of the S-alkylated and S-alkylphthalimidated oxadiazole derivatives against DENV-2.

Fig. 36

SAR of the oxadiazole scaffolds.