- Tuning the activity of known drugs via the introduction of halogen atoms, a case study of SERT ligands – Fluoxetine and fluvoxamine
-
The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42, SERT Ki = 5 nM and 3,4-diCl-fluvoxamine 46, SERT Ki = 9 nM, fluoxetine SERT Ki = 31 nM, fluvoxamine SERT Ki = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. ‘XSAR library analysis’, a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution.
- Bojarski, Andrzej J.,Bugno, Ryszard,Duszyńska, Beata,Hogendorf, Adam S.,Hogendorf, Agata,Kurczab, Rafa?,Lenda, Tomasz,Pietru?, Wojciech,Sata?a, Grzegorz,Staroń, Jakub,Wantuch, Anna,Warszycki, Dawid
-
supporting information
(2021/06/02)
-
- 1 - Trifluoromethyl tolyl -5 - methoxy - pentanone synthetic method
-
The invention discloses a 1 - trifluoromethyl tolyl - 5 - methoxy - pentanone synthetic method, the specific synthetic process are as follows: in a reaction container by adding sodium hydroxide solution, heating to 70 - 80 °C added after the reaction to the trifluoromethyl phenyl nitrile 10 h after lowering the temperature to 65 °C, then added to the reaction container in the methanol solution stirring reaction 2 h after cooling to room temperature, then liquid, takes organically phase is trifluoromethyl methyl benzoic acid methyl ester; under the protection of nitrogen, in the flask to adding anhydrous tetrahydrofuran and continously, and add a few drops of iodomethane, heating up to 75 °C, stirring to dissolve and drip into the 1 - chloro - 4 - methoxy butane, after dropping the constant temperature reaction 13 h, cooling to room temperature dropwise added after step 1 in preparation to the trifluoromethyl benzoic acid methyl ester to obtain the product. The invention preparation of trifluoromethyl methyl benzoic acid methyl ester with compared to the trifluoromethyl phenyl nitrile, in the reagent in the reaction process with the format of the mild reaction conditions, and reaction process is easy to control, of a complete reaction, the yield of the product is high.
- -
-
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF FLUVOXAMINE MALEATE
-
The present invention relates to an industrially feasible and economically viable process for the preparation of fluvoxamine maleate of formula I.
- -
-
Paragraph 0048; 0049
(2016/07/05)
-
- PROCESS FOR THE SYNTHESIS AND PURIFICATION OF (4-METHOXYBUTYL) (4-TRIFLUOROMETHYLPHENYL)METHANONE
-
A new process for the preparation of 4-trifluoromethylvalerophenone is described. The process described is a three step process comprising the synthesis of organomagnesium specie, coupling reaction between the of organomagnesiurn specie and trifluoromethylbenzonitrile or trifluoromethylbenzoyl chloride and preferably a purification of the product obtained in suitable reaction conditions. In the process an extraction phase of the final product is not required.
- -
-
Page/Page column 11-12
(2008/06/13)
-
- Process for the synthesis of alkoxyalkyl (trifluormethylphenyl) methanones
-
A new process is described for the preparation of (alkoxyalkyl)(4-trifluoromethylphenyl)methanones. The process comprises reacting a 4-trifluoromethylbenzonitrile with an alkoxyalkyl Grignard in the presence of a suitable polar aprotic solvent. The compound (4-methoxybutyl)(4-trifluoromethylphenyl)methanone is useful as an intermediate in the preparation of the antidepressant drug fluvoxamine.
- -
-
-
