Research Projects

Frequent re-emergence of vector borne infections, Chikungunya and Dengue, present a major health threat to the human population worldwide and puts a huge global economic burden. India, being a densely populated country is prone to infection outbreak. Unavailability of an approved vaccine for Chikungunya (CHIKV) and Dengue (DENV) viruses renders the situation vulnerable, demanding an urgent development of effective drugs. Quinoline is a ‘privileged scaffold’ in medicinal chemistry d remains the preferred pharmacophores in the antiviral drug design. Quinoline-derived antimalarial drug, chloroquine was reported to inhibit CHIKV and DENV, revealing the potential of quinoline pharmacophore against these viruses. Nucleoside analogs are another important class of broad-spectrum antivirals that have shown potency against CHIKV and DENV. In some studies, the conjugation of nucleoside scaffolds to the bioactive molecules was shown to significantly improve their bioactivity. Owing to the potent antiviral effects of quinolines and nucleosides against CHIKV and DENV, the novel quinoline-purine nucleoside (adenosine and deoxyadenosine) conjugates are proposed as effective CHIKV and DENV inhibitors. In a preliminary study, a reaction of adenosine with quinoline N-oxide in the presence of tert-butylnitrite gave the novel adenosine-quinoline N-oxide conjugate. In first phase of the study, this environmental friendly approach will be used to access a library of novel adenosine and deoxyadenosine conjugates of quinoline N-oxides. Direct deacetylation of sugar alcohols will provide the nucleoside-quinoline N-oxides (Type 1 conjugates). Further, N-deoxygenation using Zn dust will give nucleoside-quinoline conjugates (Type 2 conjugates). Next, using our recently developed approach; Type 1 conjugates will be converted to C-3-phenyl-C-2-nucleoside-quinolines ((Type 3 conjugates). Using this approach, the purine nucleoside conjugates of the chloroquine and hydroxychloroquine will also be prepared. In second phase, the molecular docking studies of the structures of conjugates will be performed with viral proteins nsP1 (CHIKV) and NS5 (DENV) to understand their interactions with the target biomolecules and to assess the structure activity relations for designing effective inhibitors. In third phase, protein inhibition using recombinant viral target enzymes enzymatic activity will be performed in the presence of identified inhibitors by the assays. The hit compounds screened through both these assays will also be validated for binding to the target protein using biophysical techniques including circular dichroism, isothermal calorimetry and surface plasmon resonance. In fourth phase, the antiviral activities will be assessed through the cell-based antiviral assays. The previously isolated strains in our group will be used to evaluate the antiviral activity of the molecules by observing the cytopathic effect on virus-infected cells and by performing plaque reduction assay.