title: Synthesis and structure elucidation of novel fused 1,2,4-triazine derivatives as potent inhibitors targeting CYP1A1 activity.
abstract: Synthesis and structure elucidation of new series of novel fused 1,2,4-triazine derivatives 3a-3f, 4a-4i and 6a-6b and their inhibitory activities are presented. Molecular structures of the synthesized compounds were confirmed by (1)H NMR, (13)C NMR, MS spectra and elemental analyses. X-ray crystallographic analysis was performed on 2-acetyl-8-(N,N-diacetylamino)-6-(4-methoxybenzyl)-3-(4-methoxy-phenyl)-7-oxo-2,3-dihydro-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazine 3d and 2-acetyl-8-(N-acetylamino)-6-benzyl-3-(4-chlorophenyl)-3-methyl-7-oxo-2,3-dihydro-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazine 4e to secure their structures. The inhibitory effect of these compounds toward the CPY1A1 activity was screened to determine their potential as promising anticancer drugs. Our data showed that compounds 4e, 5a, 5b and 6b possess the highest inhibitory effects among all tested compounds. Furthermore, analysis of triazolotriazine derivatives docking showed that these compounds bind only at the interface of substrate recognition site 2 (SRS2) and (SRS6) at the outer surface of the protein. Amino-acids ASN214, SER216 and ILE462 participate in the binding of these compounds through H-bonds.
authors.affiliation: Department of Chemistry, Rabigh College of Science and Art, King Abdulaziz University, Saudi Arabia.
authors.forename: Abdel Moneim
authors.initials: AM
authors.lastname: El Massry
authors.forename: Ahmed Mosaad
authors.initials: AM
authors.lastname: Asal
authors.forename: Sherine Nabil
authors.initials: SN
authors.lastname: Khattab
authors.forename: Nesreen Saied
authors.initials: NS
authors.lastname: Haiba
authors.forename: Hala A
authors.initials: HA
authors.lastname: Awney
authors.forename: Mohamed
authors.initials: M
authors.lastname: Helmy
authors.forename: Vratislav
authors.initials: V
authors.lastname: Langer
authors.forename: Adel
authors.initials: A
authors.lastname: Amer
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014227:Triazines; C093444:1,2,4-triazine; D019363:Cytochrome P-450 CYP1A1