Supplementary material for the article: Lazić, A. M.; Mašulović, A. D.; Lađarević, J. M.; Valentić, N. V. Assessing the pharmacological potential of selected xanthene derivatives. Journal of the Serbian Chemical Society 2023, 88(9), 811-824. https://doi.org/10.2298/JSC230131035L

A convenient and efficient approach toward the synthesis of seven aromatically substituted xanthendiones 1‒7 and one structurally-related xanthenone 8 through condensation of dimedone and the appropriate aromatic aldehyde is reported. Further, their chemical structure was confirmed by melting points, elemental analysis, FT-IR, 1H-, 13C-NMR and UV–Vis spectroscopic methods. The relationship between the chemical structure and pharmacological activity was determined empirically using appropriate software packages and in vitro using the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) method. The results of in silico prediction suggested that all investigated compounds possess good oral bioavailability. The results of the ABTS assay indicate that five compounds possess the ability to scavenge the ABTS•+ radical cation. Based on the comparison of the IC50 values, the activity of the compounds was found to be as follows: 6 > 1 > 7 > 2 > 8. The effects of solvent dipolarity/polarizability and solute solvent–hydrogen-bonding interactions on the shifts of the absorption maxima were rationalized by means of the linear solvation energy relationship concepts proposed by Kamlet–Taft and Catalán.Related to: [https://technorep.tmf.bg.ac.rs/handle/123456789/6809]Supplementary material for: [https://doi.org/10.2298/JSC230131035L

Sinteza 5-(supstituisanih fenilazo)-6-hidroksi-4-metil-3-cijano-2-piridona iz etil-3-okso-2-(supstituisanih fenilazo)butanoata

A new procedure for the synthesis of known azo pyridone dyes is presented. A series of 5-(substituted arylazo)-6-hydroxy-4-methyl-3-cyano-2-pyridones were prepared from ethyl 3-oxo-2-(substituted phenylazo)butanoates and cyanoacetamide in acetone using potassium hydroxide as a catalyst by simple refluxing the reaction mixture. The structure of these dyes was confirmed by FT-IR, NMR and UV-Vis spectroscopy.Novi postupak za sintezu poznatih azo-piridonskih boja je opisan u radu. Serija 5-(supstituisanih fenilazo)-6-hidroksi-4-metil-3-cijano-2-piridona je pripremljena iz etil-3-okso-2-(supstituisanih fenilazo)butanoata i cijanoacetamida u acetonu korišćenjem kalijum-hidroksida kao katalizatora uz zagrevanje

Synthesis, structure and solvatochromic properties of some novel 5-arylazo-6-hydroxy-4-phenyl-3-cyano-2-pyridone dyes

Background: A series of some novel arylazo pyridone dyes was synthesized from the corresponding diazonium salt and 6-hydroxy-4-phenyl-3-cyano-2-pyridone using a classical reaction for the synthesis of the azo compounds. Results: The structure of the dyes was confirmed by UV-vis, FT-IR, H-1 NMR and C-13 NMR spectroscopic techniques and elemental analysis. The solvatochromic behavior of the dyes was evaluated with respect to their visible absorption properties in various solvents. Conclusions: The azo-hydrazone tautomeric equilibration was found to depend on the substituents as well as on the solvent. The geometry data of the investigated dyes were obtained using DFT quantum-chemical calculations. The obtained calculational results are in very good agreement with the experimental data

In vitro antioxidant activity evaluation of selected xanthene derivatives

Xanthendiones (1,8-dioxooctahydroxanthenes) are a special class of oxygenincorporating tricyclic compounds bearing as a basic feature a pyran nucleus fused on either side with cyclohex-2-enone rings. They are often found as a structural motif in natural products with a wide range of biological activities, such as: antioxidant, antimicrobial, trypanocidal, antiinflammatory, antiproliferative and anticancer. A convenient and efficient approach toward the synthesis of seven aromatically substituted xanthendiones 1‒7 and one structurally-related xanthenone 8 through condensation of dimedone and the appropriate aromatic aldehyde is reported. The relationship between the chemical structure and pharmacological activity was determined empirically using appropriate software packages and in vitro using the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) method. The results of the ABTS assay indicate that five compounds possess the ability to scavenge the ABTS•+ radical cation. Based on the comparison of the IC50 values, the activity of the compounds was found to be as follows: 6 > 1 > 7 > 2 > 8

Synthesis, structure and solvatochromism of 5-methyl-5-(3- or 4-substituted phenyl)hydantoins

Several 5-methyl-5-(3- or 4-substituted phenyl)hydantoins were prepared and their ultraviolet absorption spectra were recorded in the region 200–400 nm in twelve solvents of different polarity. The effect of solvent dipo¬larity/polarizability and solvent/solute hydrogen bonding interactions were analyzed by means of the linear solvation energy relationship (LSER) concept proposed by Kamlet and Taft. The lipophilic activity of the investigated hydantoins was estimated by calculation of log P values with Advanced Chemistry Development Software. The calculated values of log P were correlated with the contribution of hydrogen bond donor–solvent interactions. By employing the thus obtained linear dependence, the pharmacological activity of the studied hydantoin derivatives is discussed

Oxaprozin: Synthesis, SAR study, physico-chemical characteristics and pharmacology

Oxaprozin (3-(4,5-difeniloksazol-2-yl)propanoic acid) is a nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of numerous inflammatory musculoskeletal diseases, including rheumatoid arthritis, osteoarthritis, tendonitis, ankylosing spondylitis and bursitis. It is the first representative member of the diaryl-substituted heterocyclic compounds, which have found clinical use as selective cyclooxygenase-2 (COX-2) inhibitors. U.S. Food and Drug Administration (FDA) approved its official use in 1992. Both anti-inflammatory and analgesic properties of oxaprozin are mainly due to the potent inhibition of COX. However, oxaprozin-induced benefits might be also regulated by other COX-independent pathways. It has been shown that oxaprozin induced direct proapoptotic effects in CD40L-treated human monocytes independently of COX inhibition. It also has several advantages in the treatment of inflammatory diseases in comparison to other NSAIDs such as aspirin, naproxen, indomethacin and phenylbutazone, which enabled oxaprozin to become one of the most used NSAIDs in America. Oxaprozin, as other members of the group of NSAIDs, can cause gastrointestinal complications, but significantly lower due to relatively high pKa value. In this paper, importance of oxaprozin in the treatment of arthritis and its pharmacokinetic properties were described, therewith its activity and side effects were compared with other commercially available anti-inflammatory drugs

Synthesis, structure and solvatochromic properties of 3-cyano--4,6-diphenyl-5-(3- and 4-substituted phenylazo)-2-pyridones

Abstract: A series of some new pyridone arylazo dyes was synthesized from the corresponding diazonium salts and 3-cyano-4,6-diphenyl-2-pyridone using the classical reaction for the synthesis of the azo compounds. The structures of these dyes were confirmed by UV–Vis, FT-IR and 1 H-NMR spectroscopic techniques. The solvatochromism of the dyes was evaluated with respect to visible absorption properties in various solvents. The effects of solvent dipolarity/polarizability and solvent/solute hydrogen bonding interactions were analyzed by means of the linear solvation energy relationship concept proposed by Kamlet and Taft. The 2-pyridone/2-hydroxypiridine tautomeric equilibration was found to depend on the substituents as well as on the solvents

Solvent effects on the absorption spectra of potentially pharmacologically active 5-alkyl-5-arylhydantoins: A structure-property relationship study

To obtain an insight into the interactions of potential anticonvulsant drugs with their surrounding, two series of 5-methyl-5-aryl- and 5-ethyl-5-arylhydantoins were synthesized and their absorption spectra were recorded in the region from 200 to 400 nm in a set of selected solvents. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen bonding interactions on the absorption maxima shifts were analyzed by means of the linear solvation energy relationship (LSER) concept of Kamlet and Taft. The ratio of the contributions of specific and nonspecific solvent-solute interactions were correlated with the corresponding ADME properties of the studied compounds. The correlation equations were combined with different physicochemical parameters to generate new equations, which demonstrate the reasonable relationships between solvent-solute interactions and the structure-activity parameters. [Projekat Ministarstva nauke Republike Srbije, br. 172013

Quntum mechanical and spectroscopic (FT-IR, C-13, H-1 NMR and UV) investigations of potent antiepileptic drug 1-(4-chloro-phenyl)-3-phenyl-succinimide

This study represents an integrated approach towards understanding the vibrational, electronic, NMR, and structural aspects, and reactivity of 1-(4-chloro-phenyl)-3-phenyl-succinimide (CPPS). A detailed interpretation of the FT-IR, UV and NMR spectra were reported. The equilibrium geometry, bonding features, and harmonic vibrational frequencies have been investigated with the help of density functional theory (DFT) B3LYP method using 6-31G(d,p) and 6-311++G(d,p) basis set. The scaled theoretical wave-number showed very good agreement with the experimental values. The H-1 and C-13 nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by the Gauge-Invariant Atomic Orbital (GIAO) method. Stability of the molecule, arising from hyperconjugative interactions and charge delocalization, has been analyzed using Natural Bond Orbital (NBO) analysis. The results show that ED in the sigma* and pi* antibonding orbitals and second order delocalization energies E(2) confirm the occurrence of intramolecular charge transfer (ICT) within the molecule. UV-Vis spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies, were calculated by Time-Dependent (TD-DFT) approach. To estimate chemical reactivity of the molecule, the molecular electrostatic potential (MEP) surface map is calculated for the optimized geometry of the molecule