Atovaquone

IUPAC: 2 - [ trans-4- ( 4-chlorophenyl) cyclohexyl] -3 - -hydroxy-1 ,4-naphthoquinone

P01AX06

Antiprotozoals

222 ° C ( polymorph III)

Practically insoluble in water

Template: Infobox chemical / molecular formula search available

Atovaquone is a drug that is used for the treatment of protozoal diseases such as malaria and toxoplasmosis, and caused by the fungus Pneumocystis carinii pneumocystis pneumonia (PCP). Its mechanism of action is based on a structure by analogy to ubiquinone (coenzyme Q) -induced disruption of nucleic acid synthesis of the pathogen. Atovaquone is offered by the company GlaxoSmithKline as a single agent under the brand name Wellvone ® for the treatment of Pneumocystis pneumonia and in combination with proguanil under the brand name Malarone for chemoprophylaxis and treatment of malaria. Atovaquone is subject to medical prescription.

Synthesis

The synthesis of atovaquone starts with a Friedel- Crafts acylation of chlorobenzene by means of acetyl chloride in the presence of cyclohexene. The resulting Chlorphenylcyclohexylmethylketon is oxidized with bromine to substituted cyclohexane carboxylic acid. In the third step, an oxidative coupling with 2-chloro- 1 ,4-naphthoquinone. The target molecule is obtained by the subsequent hydrolysis with methanolic sodium hydroxide solution.

Properties

Atovaquone is a yellowish crystalline solid, which can occur in three polymorphic forms. Form I shows during heating at 197 ° C an enantiotropic transformation into the form III. A similar behavior shows the Form II, which enantiotropically already at 169 ° C converts to Form III. Form III shows up to the melting point at 222 ° C, no solid phase transformation. The enthalpy of fusion is 35 kJ · mol -1. Forms I and II relate to each other monotropically. At room temperature, the form I is the thermodynamically stable form. All three forms may be obtained by means of a solvent of crystallization. Forms I and III form both a monoclinic crystal system and differ with respect to the space group P21 / n for I and P21 / c for III.