Discovery of a novel DNA binding agent via design and synthesis of new thiazole hybrids and fused 1,2,4-triazines as potential antitumor agents: Computational, spectrometric and in silico studies

[Display omitted] •Twenty-two target compounds have been designed and synthesized.•Five derivatives were evaluated against NCI 60 cancer cell lines.•3d stood as broad spectrum antitumor agent with GI50 MG-MID = 14.22 µM.•Compare and MEP for 3d revealed similar mechanism of action to Clomesone.•Fluorescence and UV–Vis spectrometric measurements confirmed anticancer activity of 3d via DNA binding. New series of furan–thiazole hybrids (3a-f), thiazolo[2,3-c]-1,2,4-triazines (4a-f), their bioisosteres 1,3,4-thiadiazolo[2,3-c]-1,2,4-triazines (8a-d) and 1,2,4-triazino[4,3-b]-1,2,4-triazines (13a-e) were designed, synthesized and evaluated for their in vitro antitumor activities at the National Cancer Institute (NCI, USA). Among the synthesized compounds, 3d was found to exhibit promising broad spectrum antitumor activity (GI50 MG-MID = 14.22 µM) in a five-dose assay against the full panel NCI-cancer cell lines. 3d displayed higher antitumor activity against most tested cancer cell lines than 5-FU as reference. COMPARE analysis and molecular electrostatic potential computational study revealed that 3d probably exerts its antitumor properties through DNA binding similar to Clomesone. Further DNA binding studies using fluorescent terbium (Tb+3) probe revealed increased fluroresence of DNA-3d-Tb+3 mixture due to damage of the double-stranded DNA. Also, UV–vis absorption study was conducted which showed hyperchromic shift in DNA absorption confirming 3d-induced DNA damage. The assessed potency of 3d-induced DNA damage of calf thymus DNA showed a concentration as low as 2.04 ng/mL for a detectable DNA damage. Moreover, in silico calculation of physicochemical properties and druglikeness were in compliance to Lipinski’s rule.