Structural Chemistry, Vol. 11, No. 4, 2000 1040-0400 / 00 / 0800-0249$18.00 / 0  2000 Plenum Publishing Corporation 249 Synthesis, X-ray Molecular Structure, and Semiempirical Calculations of a New Heteroarylpiperazine Derivative Ernesto Estrada, 1,2 Jos ´ e C. Gonz ´ alez, 2 Lourdes Santana, 2 Eugenio Uriarte, 2,4 and Alfonso Casti ˜ neiras 3 Received November 11, 1999; accepted April 14, 2000 The new piperazine derivative (1) was synthesized by linking a coumarin system to a heteroarylpiperazine via a propyloxy chain. Its molecular structure, as determined by X-ray diffractometry is compared to those computed by three semiempirical methods. PM3 and MNDO give the best accuracy in reproducing the bond distances and angles, respectively. AM1 gives the best agreement with X-ray in reproducing the whole three-dimensional (3D) structure of this molecule. An analysis of these results at the light of other similar previously reported is carried out. KEY WORDS: Piperazines; coumarins; synthesis; X-ray crystallography; semiempirical methods. INTRODUCTION The discovery that serotonin (5-HT) is implicated in several behavioral disorders, including anxiety, depres- sion, and insomina [1], has led to an intensive search for compounds that interact with serotonin receptors. Sev- eral aryl- and heteroarylpiperazine derivatives have been identified as agonists (flesinoxan), partial agonists (bus- pirone) or antagonists [(S)-WAY-100135)] of the type 1A serotonin receptor (5-HT 1A ) [2–4]. Structure–activity studies have shown that substitution at N4 of the arylpiperazine increased affinity for 5-HT 1A [5]. Lipo- philicity five bonds from N4 seems to increase affinity for both 5-HT 1A and D2 [6]. It has also been shown that the 3-D structure of this class of molecules can modulate 5-HT 1A / D2 selectivity [7]. According to the last finding related to the con- formational preferences of these molecules, it is inter- 1 Departamento de Farmacia, Facultad de Qu´ ımica y Farmacia, Uni- versidad Central de Las Villas, Cuba. 2 Departamento de Qu´ ımica Org´ anica, Facultad de Farmacia, Univer- sidad de Santiago de Compostela, Spain. 3 Departamento de Qu´ ımica Inorg´ anica, Universidad de Santiago de Compostela, Spain. 4 To whom correspondence should be addressed: email: qofuri@usc.es esting to investigate the 3-D structure of novel het- eroarylpiperazines by using both experimental and theo- retical approaches. The computational methods offer an alternative to the prediction of the 3-D molecular struc- ture of chemical compounds. Different levels of calcu- lation can be selected for use, taking into account the size of the molecules and the precision needed for the results among others. While molecular mechanic (MM) approaches [8] are very fast and permit the calculation of the 3-D structure for relatively large molecules, the results do not include the calculation of important elec- tronic parameters of the molecules that could be useful in further developing quantitative structure–activity rela- tionships. The most accurate ab initio calculations are very time consuming for large molecules and their use in the study of large data sets of molecules for develop- ing structure–activity relationships is almost prohibitive [9]. An intermediate level of accuracy is provided by the so-called semiempirical quantum chemical calculations. Among these methods, the rapid, inexpensive and user- friendly AM1 and PM3 are probably the most popular ones [10, 11]. Several studies have been dedicated to compare AM1 and PM3 methods as well as to compare other