THE STRUCTURAL STUDIES ON 2-SUBSTITUTED ISOTHIAZOLOPYRIDINES

Z. Karczmarzyk1 and W. Malinka2

1 Department of Chemistry, Agricultural and Teachers University, ul. 3 Maja 54, PL - 08 110 Siedlce, Poland.
2 Department of Chemistry of Drugs, University of Medicine, ul. Tamka 1, PL - 50 137 Wroclaw, Poland.

Keywords: isothiazolopyridines, crystal and molecular structure, conformational analysis

The crystal and molecular structure of 4,6-dimethyl-2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]isothiazolo[5,4-b]pyridin-3(2H)-one, (II), is presented, as part of a larger structural and pharmacological study on a series of 2-substituted isothiazolopyridines of general structure (I).


The pharmacological investigation data of the compounds (I) in vivo suggest that the profile of biological activity is characteristic for an agonist of the receptors 5-HT-2A. Of particular interest with respect to an anorectic and potential antidepresive action , is the most active in the series compound (III) [1], which was chosen as a pharmacophore system for other isothiazolopyridine derivatives in structure-activity relationship studies.

The principal aims of structure determination of the derivative (II) were to establish the conformation of substituent in position 2, the changes in the geometrical parameters of the molecular skeleton in comparison to those observed in molecule of (III) [2] and especially the influence of the ortho-substituent in N-phenylpiperazine on deformation of piperazine ring and conjugation of the lone pair at N atom with the p system of the phenyl ring.

The crystallographic data of (II) and (III) were used as starting models to modeling all molecules of the investigated 2-substituted isothiazolopyridine derivatives for conformational analysis performed by molecular mechanics and semiempirical methods. The electronic properties as: distribution of atomic net charge, direction and length of dipole moment vectors and reactivity factors were calculated and involved in the interpretation of the chemical and pharmacological properties of molecules.

  1. W. Malinka & M. Rutkowska, Il Farmaco 52 (1997) 595 - 601.
  2. Z. Karczmarzyk & W. Malinka, Acta Cryst. C54 (1998) in press.