Design, Synthesis, Molecular Modeling Study and Biological Evaluation of New N'-Arylidene-pyrido [2,3- d]pyrimidine-5-carbohydrazide Derivatives as Anti-HIV-1 Agents

Abstract

In an attempt to identify potential new agents that are active against HIV-1, a series of novel pyridopyrimidine-5-carbohydrazide derivatives featuring a substituted benzylidene fragment were designed and synthesized based on the general pharmacophore of HIV-1 integrase inhibitors. The cytotoxicity profiles of these compounds showed no significant toxicity to human cells and they exhibited anti-HIV-1 activity with EC50 values ranging from 90 to 155 µM. Compound 5j bearing 4-methylbenzylidene group was found to be the most active compound with EC50 = 90 µM and selectivity index, CC50/EC50 = 6.4. Molecular modeling studies indicated the capacity of compound 5j to interact with two Mg2+ cations and several residues that are important in HIV-1 integrase inhibition. These findings suggested that pyridopyrimidine-5-carbohydrazide scaffold might become a promising template for development of novel anti-HIV-1 agents.

Keywords: Anti-HIV-1; HIV-1 integrase; Molecular modeling; Pyridopyrimidine-5-carbohydrazide; Synthesis.

Figure 1.

FDA-approved HIV integrase inhibitors (Raltegravir, Elvitegravir, Dolutegravir), HIV IN inhibitors (A and B) and our designed molecule

Figure 2

Route of synthesis

Figure 3

a) 3D alignment of best docked conformer of compound 5j (shown in yellow) and b) 2D alignment of best docked conformer of compound 5j in the PFV IN active site

Figure 4

a) Interaction of compound 5j (shown in yellow) and Raltegravir (shown in green) with the surface of PFV IN active site, b) 2D Superimposition of compound 5j (shown in green) on Raltegravir (shown in red) in the PFV IN active site