Conformational Properties and Putative Bioactive Targets for Novel Thiosemicarbazone Derivatives

Nikitas Georgiou; Antigoni Cheilari; Danai Karta; Eleni Chontzopoulou; Janez Plavec; Demeter Tzeli; Stamatia Vassiliou; Thomas Mavromoustakos

doi:10.3390/molecules27144548

Conformational Properties and Putative Bioactive Targets for Novel Thiosemicarbazone Derivatives

Molecules. 2022 Jul 16;27(14):4548. doi: 10.3390/molecules27144548.

Authors

Nikitas Georgiou¹, Antigoni Cheilari², Danai Karta¹, Eleni Chontzopoulou¹, Janez Plavec³, Demeter Tzeli^{4

5}, Stamatia Vassiliou¹, Thomas Mavromoustakos¹

Affiliations

¹ Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis Zografou, 11571 Athens, Greece.
² Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.
³ Slovenian NMR Centre, National Institute of Chemistry, SI-1001 Ljubljana, Slovenia.
⁴ Laboratory of Physical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis Zografou, 11571 Athens, Greece.
⁵ Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., 11635 Athens, Greece.

Abstract

The structure assignment and conformational analysis of the thiosemicarbazones, DKI21 and DKI24, were performed through homonuclear and heteronuclear 2D Nuclear Magnetic Resonance (NMR) spectroscopy (2D-COSY, 2D-NOESY, 2D-ROESY, 2D-HSQC, and 2D-HMBC) and quantum mechanics (QM) calculations, using Functional Density Theory (DFT). In addition, utilizing a combination of 2D-NOESY and 2D-ROESY spectra an exo structure was established for both of the analogs. This experimental results were confirmed by theoretical mechanistic studies, as the lowest minima conformations derived through DFT calculations were compatible with the spatial correlations observed in the 2D-NOESY and 2D-ROESY spectra. Finally, molecular binding experiments were performed to detect the potential targets for DKI21 and DKI24, derived from SwissAdme. In silico molecular binding experiments showed favorable binding energy values for the most of the enzymes studied. The ADMET calculations, using the preADMET and pKCSm software, showed that the two molecules appear as possible drug leads.

Keywords: DFT; NMR spectroscopy; molecular binding; quantum mechanics; thiosemicarbazones.

MeSH terms

Magnetic Resonance Spectroscopy
Molecular Conformation
Nuclear Magnetic Resonance, Biomolecular / methods
Software
Thiosemicarbazones*

Substances

Thiosemicarbazones

Grants and funding

J.P. acknowledges financial support of the Slovenian Research Agency [Grants Nos. P1-0242 and J1-1704]. The authors acknowledge the CERIC-ERIC 20217107 consortium for the access to experimental facilities and financial support.