title: Quinazolinone-benzimidazole conjugates: Synthesis, characterization, dihydrofolate reductase inhibition, DNA and protein binding properties.
abstract: Quinazolinone and benzimidazole represent as important and abundant classes of fused nitrogen-containing heterocycle. A series of two isomeric quinazolinone-benzimidazole conjugates is synthesized and substitutes with different aromatic rings. These compounds are well characterized by1H and13C NMR as well as mass spectrometry. Compounds are then evaluated by dihydrofolate reductase inhibitory activity. In vitro assay shows that some compounds are exhibiting significant dihydrofolate reductase inhibitory activities. Compound 14 shows comparable or even superior inhibitory activity with IC50value of 0.011μM in contrast to methotrexate (IC50=0.02μM). The preliminary interactive investigation of compound 14 is studied with calf thymus DNA by UV-visible and fluorescence spectroscopy. It reveals that compound 14 is effectively intercalated with ct-DNA to form 14.DNA complex which is further supported by ethidium bromide (EB) displacement studies. The compound 14 also shows strong interaction with bovine serum albumin that can helpful in the design, modification and screening of drug molecules. The binding interactions of compound 14 with bovine serum albumin demonstrate that hydrogen bonds and van der Waals forces play important roles in the strong association of compound 14.BSA. These compounds can be considered as useful templates for future development and further derivatization or modification will be helpful to obtain more potent compounds.
authors.affiliation: School of Chemistry and Biochemistry, Thapar University, Patiala 147 001, India.
authors.forename: Prinka
authors.initials: P
authors.lastname: Singla
authors.affiliation: School of Chemistry and Biochemistry, Thapar University, Patiala 147 001, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Luxami
authors.affiliation: School of Chemistry and Biochemistry, Thapar University, Patiala 147 001, India. Electronic address: kpaul@thapar.edu.
authors.forename: Kamaldeep
authors.initials: K
authors.lastname: Paul
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry*; D004247:DNA / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry; D011485:Protein Binding; D052999:Quinazolinones / Q000737:chemistry*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D005493:Folic Acid Antagonists; D007364:Intercalating Agents; D052999:Quinazolinones; D012710:Serum Albumin, Bovine; D004247:DNA
keywords: Benzimidazole; Bovine serum albumin; Calf thymus DNA; DHFR; Quinazoline