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Dengue virus poses a serious worldwide health threat with up to 400 million infections occurring annually in over 100 countries. Currently, there are no specific therapeutics available, and the only licensed vaccine encompasses risk of hospitalization in immunologically naive individuals. In the current work for the first time we are reporting dengue virus type 2 (DENV2) inhibitory activity of newly designed 3-chlorobenzyl linked 1,9-diazaspiro[5.5]undecane derivatives. Compounds with substitutions featuring 2-methylbenzyl (SPO-6, EC50 = 11.43 ± 0.87 μM), 4-bromobenzyl (SPO-7, EC50 = 14.15 ± 0.50 µM), and 4-cyanobenzyl (SPO-13, EC50 = 20.77 ± 1.92 µM) groups and Ribavirin (IC50=50.9±18 µM, J. Gen. Virol.2006,87, 1947-1952) were found to be potent against DENV2 in a cell-based assay. Docking calculations identified NS5-methyltransferase as the most probable target for this series of compounds. Molecular dynamics simulations of NS5-methyltransferase reproduced the experimental binding affinity findings by yielding ΔGbind values that predicted SPO-6 to possess the most favorable binding energy of -27.2 ± 3.9 kcal/mol compared to SPO-7, SPO-13, and Ribavirin with -22.5 ± 4.7, -22.5 ± 4.6, and -20.0 ± 4.6 kcal/mol, respectively. In addition, based on Lipinski’s rule of 5 SPO-6 was found to be nontoxic and possessed a better score of drug likeness (5.87) in comparison to the standard drug ribavirin (1.72).

Designed and synthesized novel homopiperazine linked imidazo[1,2- a ]pyrimidine derivatives ( 10a–i , 11a–g , 12 ), and evaluated them for their in vitro cytotoxicity against HeLa cells (cervical cancer), A549 cells (lung cancer) cells, by MTT assay. Compound 12 (IC 50 = 4.14 µM) and compound 10c (IC 50 = 5.98 µM) were found to be 2.5 fold, and 1.74 fold more potent when compared with standard Etoposide (IC 50 = 10.44 µM), against A549 (lung cancer cells). Compound 12 also found to be 1.57 and 1.13 fold potent against DU145 (IC 50 = 6.24 µM) and HeLa (IC 50 = 6.54 µM), respectively when compared with Etoposide (DU145, IC 50 = 9.8 µM; HeLa, IC 50 = 7.43 µM). Compound 10f (IC 50 = 6.12 µM) was found to be 1.31 fold more potent than Etoposide (IC 50 = 7.43 µM) against HeLa cell lines. Moreover compounds 10a and 11a showed cytotoxicity at low micro-molar concentrations against A549 cells. Synthesized compounds were also evaluated for their antimicrobial activity by Cup plate diffusion method. Compounds 10c , 11b , 11d and 11f displayed remarkable antimicrobial activity relating to their standard drugs Gentamycin, Amphotericin B and Ampicillin. Significantly, compound 10c showed broad spectrum activity against tested microbial strains. All the designed compounds were well occupied the binding site of the colchicine and interacted with both α- and β -tubuline interface (PDB ID: 3E22 ), which demonstrates that synthesized compounds are promising tubulin inhibitors. Also, the synthesized compounds occupied the catalytic triad and adenine-binding site, in the active site of β -ketoacyl-acyl carrier protein synthase III enzyme (PDB ID: 1MZS ). The molecular docking results provided the useful information for the future design of more potent inhibitors. These preliminary results convinced further investigation and modifications on synthesized compounds aiming towards the development of potential cytotoxic as well as antimicrobial agents.

A novel method for the synthesis of 2-imino-2 H -benzo[ h ]chromenes via the sequential addition of N -chlorosuccinimide and triethylamine to 2-amino-4 H -benzo[ h ]chromenes has been established. This reaction protocol represents an efficient synthetic strategy to form iminochromene derivatives under mild reaction conditions, which utilizes readily accessible aminochromenes as starting materials and tolerates a wide range of substrates.