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A series of 7-halogeno- (X = F, Cl, Br) and 7-methoxy-substituted acetylated 6-iodo-3- O -flavonol glycosides were prepared, and evaluated for inhibitory effect in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities. 7-Bromo-2-(4-chlorophenyl)-6-iodo-4 H -chromen-4-one-3- O -2,3,4,6 -O -tetraacetyl-β- d -glucopyranoside ( 2k ) and 7-bromo-6-iodo-2-(4-methoxyphenyl)-4 H -chromen-4-one-3- O -2,3,4,6- O -tetraacetyl-β- d -glucopyranoside ( 2l ) exhibited significant inhibitory effect against AChE activity when compared to the activity of the reference standard, donepezil. Compound 2k was found to be selective against AChE and to exhibit reduced inhibitory effect against BChE activity. 6-Iodo-7-methoxy-2-(4-methoxyphenyl)-4 H -chromen-4-one-3- O -2,3,4,6- O -tetraacetyl-β- d -glucopyranoside ( 2p ) was found to exhibit increased activity against BChE, more so than the activity of donepezil. The most active compounds were also evaluated for inhibitory effect against β-secretase activity and for potential radical scavenging activities. The experimental data were complemented with molecular docking (in silico) studies of the most active compounds into the active sites of these enzymes.

In this paper, we describe the synthesis of the 5-styryltetrazolo[1,5- c ]quinazolines substituted at the 9-position with a 4-fluorophenyl ring directly or via a conjugated π-spacer (C=C or C≡C bond) based on the 6-bromo-4-chloro-2-styrylquinazoline scaffold. The structures of the synthesized compounds were characterized based on a combination of ¹H-NMR, 13 C-NMR, IR and high resolution mass spectral data as well as microanalyses. The tetrazoloquinazolines were evaluated for potential in vitro cytotoxicity against the human breast adenocarcinoma (MCF-7) and cervical cancer (HeLa) cells. The anti-proliferative assays demonstrated that the 9-bromo-5-styryltetrazolo[1,5- c ]quinazoline 3a and 9-bromo-5-(4-fluorostyryl)tetrazolo[1,5- c ]quinazoline 3b exhibit significant cytotoxicity against both cell lines. A carbon-based substituent at the 9-position resulted in complete loss of cytotoxicity against both cell lines except for the 5,9-bis(( E )-4-fluorostyryl)tetrazolo[1,5- c ]quinazoline 4e , which was found to exhibit comparable cytotoxicity to that of Melphalan (IC 50 = 61 μM) against the MCF-7 cell line with IC 50 value of 62 μM. Molecular docking against tubulin (PDB:1TUB) showed that compounds 3a , 3b and 4e bind to the tubulin heterodimer. Binding involves hydrogen bonding for 3a and 3b and halogen interactions for 4e ., Competing Interests: The authors declare no conflict of interest.