Synthesis of disubstituted pyrrolidine-2,5-dione derivatives using the microwave procedure and evaluation of their pharmacokinetically relevant properties

Abstract

Succinimide (pyrrolidine-2,5-dione) derivatives represent organic compounds with a broad spectrum of pharmacological activity. Succinimide derivatives are well known anticonvulsants (ethosuccinimide, metosuccinimide and fensuccinimide), antipsychotics, sedatives, anticancer and antiviral agents. In this work, using a modified microwave procedure, succinimide derivatives bearing a meta and/or para-substituted phenyl group in position 1 and 4 were synthetized and completely structurally characterized by melting point, FT-IR/ATR, 1H NMR, 13C NMR and UV-Vis spectra and elemental analysis. The position of the absorption maxima of newly synthesized compounds in different solvents is considered from the aspect of specific and nonspecific interactions established between the molecules. The influence of the chemical structure on the pharmacological potential of succinimide derivatives was evaluated using the "rule of five", Veber, Egan and Ghose’s empirical criteria, as well as using different in silico methods. The obtained values of molecular descriptors were then compared with the characteristic values for reference drugs such as methosuccinimide and ethosuccinimide. Calculated molecular descriptors indicate that the investigated compounds fulfill necessary empirical criteria which qualify them as interesting drug candidates.

Derivati sukcinimida (pirolidin-2,5-diona) predstavljaju organska jedinjenja širokog spektra farmakološke aktivnosti. Derivati ovog jedinjenja poznati su antikonvulzivi (etosukcinimid, metosukcinimid i fensukcinimid), antipsihotici, sedativi, antikancerogeni i antivirusni agensi. U okviru ovog rada, primenom modifikovanog mikrotalasnog postupka, sintetisani su pirolidin-2,5-dioni koji u položajima 1 i 4 sadrže meta i/ili para-supstituisanu fenil-grupu. Njihova struktura potvrđena je određivanjem temperature topljenja, primenom FT-IR/ATR, 1H NMR, 13C NMR i UV-Vis spektroksopskih metoda i elementarne analize. Položaj apsorpcionih maksimuma novosintetisanih jedinjenja u različitim rastvaračima razmatran je sa apsekta specifičnih i nespecifičnih interakcija koje se uspostavljaju između molekula rastvorene supstance i molekula rastvarača. Uticaj hemijske strukture na farmakološki potencijal derivata pirolidin-2,5-diona, procenjen je primenom „pravila broja pet“, Veberovog, Eganovog i Gozovog emirijskog kriterijuma, kao i primenom različitih in silico metoda. Dobijene vrednosti molekulskih deskriptora potom su upoređene sa vrednostima karakterističnim za referentne lekove kao što su metosukcinimid i etosukcinimid. Dobijene vrednosti molekulskih deskriptora ukazuju da proučavana jedinjenja zadovoljavaju sve empirijske kriterijume neophodne za dalja ispitivanja lekova.