Conformational Analysis of a Thiosemicarbazone Derivative Having in Vitro Antimicrobial Activity by Molecular Mechanics and Ab Initio Methods

Compounds having indoline-thiosemicarbazone moiety within their structure display biological activity against a wide range of biological targets, being used in clinical practice as anticancer and antiviral agents. The generation of low-energy conformers is extremely important for various computational chemistry applications, such as 3D QSAR, pharmacophore searches, ligand-receptor docking, and 3D database searching. This paper presents the study of the conformational space of 1-{[5-fluoro-2-oxo-1-(piperidin-1-ylmethyl)-2,3-dihydro-1H-indol-3-ylidene]amino}-3-(prop-2-en-1-yl)thiourea by molecular mechanics and ab initio calculations using the Omega (OMEGA (version 2.4.6), OpenEye Science Software, Santa Fe, USA, 2010), respectively the Gaussian 2009 (http://www.gaussian.com/) software. 219 Z and E isomers were generated by the MMFF94s force field included in the Omega program. They were further energy minimized by Restricted Hartree-Fock (RHF/3-21G) calculations. All optimized structures were characterized as true minima by frequency calculations (Nimag = 0 for each compound). The generated conformers have been compared by the root-mean-square-deviation (RMSD) overlay procedure with the X-ray structure of the compound. In both cases (molecular mechanics and ab initio calculations) the Z conformer with the lowest RMSD fit value was different from the lowest energy conformer. Also, a chair shape for the piperidine ring and a planar indole–thiosemicarbazone moiety was found by both methods. The formation of one intramolecular hydrogen bond has been noticed in both cases. The RMSD fit values were lower in case of Omega conformers and the difference between the highest and lowest energy conformer was smaller in case of ab initio calculations.