Binding Properties of Aromatic Carbon-Bound Fluorine

Abstract

A systematic computational analysis of the ability of aromatic carbon-bound fluorine to participate in hydrogen bonding and electrostatic interactions has been completed. The interaction energies between the most common fluoroaromatics used in medicinal chemistry and both water, the prototypical hydrogen bond donor, and several cations have been calculated at different levels of theory (HF, MP2, DFT). Our results show that aromatic fluorine can participate in significant hydrogen bonds and can also interact with charged molecules.

Synthesis and antiproliferative activity of 2-(([1,2,4]triazolo[4,3-b]- pyridazin-6-yloxy)methyl)-2,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine derivatives

“…The synthesis of target [1,2,4]triazolo [4,3-b]pyridazine compounds 14-17 is depicted in Scheme 3. The key intermediate 2-hydroxymethylbenzo[b] [1,4]oxazine derivative 9 was prepared as described, from 2-amino-5-nitrophenol 6 in three steps via i) cyclization affording ethyl 2,4-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b] [1,4]oxazine-2-carboxylate 7, ii) its Nmethylation to 8 10 and iii) subsequent borane reduction 1b of 8 (Scheme 2).…”

“…The key intermediate 2-hydroxymethylbenzo[b] [1,4]oxazine derivative 9 was prepared as described, from 2-amino-5-nitrophenol 6 in three steps via i) cyclization affording ethyl 2,4-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b] [1,4]oxazine-2-carboxylate 7, ii) its Nmethylation to 8 10 and iii) subsequent borane reduction 1b of 8 (Scheme 2). 6-Chloro- [1,2,4]triazolo [4,3-b]pyridazine 4 was also obtained by a literature procedure, involving cyclization of 3-chloro-6-hydrazinylpyridazine 3 with diethyl ethoxymethylenemalonate, 11 and cyclization of 3 with triethyl orthoacetate afforded 6-chloro-3-methyl- [1,2,4]triazolo [4,3-b]pyridazine 5 12 (Scheme 1). As depicted in Scheme 3, substitution of chlorine in [1,2,4]triazolo [4,3- After their reduction to amino derivatives 11a and 11b, N-benzylation at the aromatic amino group was carried out via imines formed with benzaldehyde, 4-fluorobenzaldehyde or 3,5-difluorobenzaldehyde, and their reduction using sodium borohydride to give compounds 12a-c and 13a-c. Acylation of amines 12 and 13 with ethyloxalyl chloride led to carboxamides 14a-c and 15a-c, respectively.…”

“…1 In an attempt to study structure-activity relationships and improve both their thrombin inhibitory activity and fibrinogen receptor binding affinity, we systematically introduced fluorine into different positions of the P3 benzyl group and replaced the basic benzamidino group present in 1 with [1,2,4]triazolo [4,3-b]pyridazine-6-yl moiety that could mimic the benzamidino part of the molecule (Figure 1). It is well documented that aromatic carbon-bound fluorine can participate in hydrogen bonding and electrostatic interactions 2 thus contributing to the binding of drug molecules to their targets.…”

“…It is well documented that aromatic carbon-bound fluorine can participate in hydrogen bonding and electrostatic interactions 2 thus contributing to the binding of drug molecules to their targets. 3 Since many potent thrombin inhibitors possessing a highly basic benzamidine moiety lack oral whereas replacement of the benzamidine functionality in 1 by [1,2,4]triazolo [4,3-b]pyridazine-6-yl group to obtain analogues 14-17, had a detrimental effect on thrombin inhibition and platelet fibrinogen receptor binding. On the contrary, the antiproliferative activity of compounds 1 studied on two endothelial (HMEC-1, BAEC) and two cancer (HELA, MCF-7) cell lines in connection with their antiangiogenic potential related to their thrombin inhibitory and fibrinogen receptor antagonistic activity, remained preserved in [1,2,4]triazolo [4,3-b]pyridazine compounds 14-17.…”

Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme

“…However, the introduction of a single fluorine atom was not expected to lead to a pronounced enhancement of activity. [27,[39][40][41] Therefore, a structural optimiziation was performed which focused on the introduction of two fluorine atoms into the benzoylic moiety (ring A; compounds 30-33), considering the following structure activity relationships obtained in previous studies: [27,28]  the OH-group on the benzoylic moiety (ring A) is very important for activity  only minor structural variations in this part are tolerated by the human target enzyme Finally, ring D was replaced with heterocycles or cyclopropyl in order to decrease the lipophilicity of the fluorinated sulfonamide compounds (compounds 34-38).…”