Experimental design optimization of RP-HPLC method for simultaneous estimation of metsulfuron-methyl, chlorantraniliprole and chlorimuron-ethyl residues in stems of Oryza sativa
Journal Article

The study aims to develop a chemometrics optimized D-optimal mixture design approach assisted RP- HPLC method for the determination of pesticide residues of metsulfuron-methyl, chlorantraniliprole, and chlorimu- ron-ethyl in the stems of Oryza sativa. Chromatographic separation was achieved on a C18 column using a mobile phase consisting of a pH 3.5 phosphate buffer and acetonitrile in the ratio 85:15.

Shanta Kumari Adiki, Prakash Katakam, Fathi H. Assaleh, (10-2021), Future Journal of Pharmaceutical Sciences: springer, 7 (217), 1-11

An Update on Therapeutic Repurposing Strategies for COVID-19
Journal Article

The severe acute respiratory syndrome coronavirus 2, well known as COVID-19 has become the current health distress to the entire world. In the pandemic scenario the research on the rapid development of new drug molecules is highly risky and tedious process. The current COVID-19 emergency demands an urgent development of possible strategies to protect people at high risk of infection and hence the drug repurposing became an emerging approach to fight COVID-19. This review summarizes an update on various therapeutic strategies with special attention on repurposing of drugs to fight against SARS-CoV-2 worldwide. The investigation of existing drugs for new therapeutic purposes is one line of scientific research followed to develop safe and effective COVID-19 treatments. Broad-spectrum antiviral agents (BSAAs) that have been believed to be safe through testing on early phase clinical trials have been hyped as good drug repurposing candidates. Broad-spectrum antiviral drugs such as Ribavirin, Umifenovir were advised for COVID-19 treatment. Some antibiotics may be repurposed as COVID-19 treatments such as teicoplanin, oritavancin, dalbavancin, monensin and azithromycin. Ivermectin an antiparasitic is recently repurposed. Hydroxychloroquine and chloroquine, having immunomodulating effect on humans, have been shown to have antiviral activity at starting and post-entry stages of the SARS-CoV-2 infection. There is a need for global health emergency to call for a courageous, global response at the political and governmental levels. Therefore, the regulatory agencies must act swiftly to lessen any financial obstacles involving private companies and update guidelines for drug licenses by repurposing if necessary.

Prakash Katakam, Shanta K. Adiki, Fathi H. Assaleh, Mohammed M. Ahmed, (04-2020), Indo Global J. Pharm. Sci.: iGlobal Research & Publishing Foundation, 10 (1), 12-18

Conformational stability of 5-substituted orotic acid derivatives analysed by measuring 13C NMR chemical shifts and applying linear free energy relationships
Journal Article

Conformational stability of various 5-substituted orotic acid derivatives was studied by applying linear free energy relationships (LFER) to the 13C NMR chemical shifts. The correlation analysis for the substituent-induced chemical shifts (SCS) with inductive (σI), and various resonance (σR) parameters were carried out through Single Substituent Parameter (SSP) and Dual Substituent Parameter (DSP) methods, and multiple regression analysis. Good Hammett correlations for all carbons were obtained, while electrophilic substituent constants better fitted for C2 carbon with electron-donor substituents. Conformational analysis of various derivatives using RB3LYP/6-311++G (3df,3dp) DFT method, together with 13C NMR data suggests that most of the substituted orotic acid derivatives exist in planar conformation, except nitro and alkyl substituted derivatives. Internal rotation of carboxylic group showed significant impact on the extent of conjugative interaction making syn conformation more stable in all the derivatives studied. Further, of all 5-substituted orotic acid derivatives, diketo form proved to be the most stable form compared to zwitterionic and enol tautomeric forms. Optimized geometries and transmission effects of particular substituent through well-defined π-resonance units suggest that these units behave as isolated as well as conjugated fragments, depending on the type of substituent

Fathi Assaleh, Aleksandar D. Marinković, Jasmina Nikolić, Nevena Ž.Prlainović, Saša Drmanić, Mohammad M.Khan, Bratislav Ž. Jovanović, (12-2019), Arabian Journal of Chemistry: Elsevier, 12 (8), 3357-3366

Solvatochromism and azo–hydrazo tautomerism of novel arylazo pyridone dyes: Experimental and quantum chemical study
Journal Article

The state of the tautomeric equilibria of eleven arylazo pyridone dyes was evaluated from UV–Vis absorption spectra with the aid of the quantum mechanical modeling. NMR analysis and theoretical calculations, by using PCM/ωB97X-D/6-311G(d,p) method, confirmed that prepared compounds exist mainly in Hydrazo form. Internal hydrogen bonding in Hydrazo tautomer, analyzed by AIM topological analysis and total electron density at the bond critical point (BCP), confirmed a presence of strong hydrogen bond which contributes to higher stability of Hydrazo form. Linear solvation energy relationships (LSERs) rationalized solvent influence on solvatochromism of all compounds in Hydrazoform and KT by using Kamlet–Taft model. Linear free energy relationships(LFERs) were applied to the substituent-induced NMR chemical shifts (SCS) using SSP (single substituent parameter) and DSP (dual substituent parameter) model. Density plots over the highest occupied (HOMO) and lowest unoccupied molecular orbitals (LUMO) energy surface provide information on the charge transfer during excitation. The molecular electrostatic potential (MEP) surface map was plotted over the optimized geometry of the molecules in order to visualize electron density distribution and explain origin of solvent/solute interactions.

Ismail Ajaj, Fathi Assaleh, Jasmina Markovski, Milica Rančić, Danijela Brkoviće, Miloš Milčić, Aleksandar D. Marinković, (12-2019), Arabian Journal of Chemistry: Elsevier, 12 (8), 3463-3478

Detailed solvent, structural, quantum chemical study and antimicrobial activity of isatin Schiff base
Journal Article

The ratios of E/Z isomers of sixteen synthesized 1,3-dihydro-3-(substituted phenylimino)-2H-indol-2-one were studied using experimental and theoretical methodology. Linear solvation energy relationships (LSER) rationalized solvent influence of the solvent–solute interactions on the UV–Vis absorption maximashifts (νmax) of both geometrical isomers using the Kamlet-Taft equation. Linear free energy relationships (LFER) in the form of single substituent parameter equation (SSP) was used to analyze substituent effect on pKa, NMR chemical shifts and νmax values. Electron charge density was obtained by the use of Quantum Theory of Atoms in Molecules, i.e. Bader's analysis. The substituent and solvent effect on intramolecular charge transfer (ICT) were interpreted with the aid of time-dependent density functional (TD-DFT) method. Additionally, the results of TD-DFT calculations quantified the efficiency of ICT from the calculated charge-transfer distance (DCT) and amount of transferred charge (QCT). The antimicrobial activity was evaluated using broth microdilution method. 3D QSAR modeling was used to demonstrate the influence of substituents effect as well as molecule geometry on antimicrobial activity

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Dominik R. Brkić, Aleksandra R. Božić, Aleksandar D. Marinković, Miloš K. Milčić, Nevena Ž. Prlainović, Fathi .H .O Assaleh, Ilija N. Cvijetić, Jasmina B. Nikolić, Saša Ž.Drmanić, (05-2018), Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy: Elsevier, 196 (5), 16-30

Multivariate assessment of azo dyes' biological activity parameters
Journal Article

Lipophilicity as key molecular descriptor of potential biological activity for selected derivatives of azo dyes was determined mathematically, by using relevant software packages and by reversed-phase thin-layer chromatography (RPTLC) on C18 and cyano modified carriers in mixtures of water/n-propanol and water/acetone. The obtained chromatographic parameters, RM0 and m, of the examined azo dyes were correlated with the standard measure of lipophilicity, log P, important pharmacokinetic predictors and selected toxicity parameters applying linear regression analysis. Thereby, good correlations for each applied system were obtained (average correlation coefficient, r, 0.944, 0.885 and 0.919). Also, the correlations between the studied parameters of azo dyes were examined applying two multivariate methods (Cluster Analysis and Principal Component Analysis). It was shown that the polarity of the substituent, and to a lesser extent its electronic effects has the greatest influence on the studied parameters of the azo dyes derivatives. Multivariate methods pointed out the similarity of the chromatographic retention constant, RM0, with the parameters of lipophilicity, unlike the chromatographic parameter m, which exhibits better agreement with the toxicity parameters.

Gyöngyi Vastag, Suzana Apostolov, Borko Matijević, Fathi Assaleh, (05-2018), Journal of Chromatography B: Elsevier, 1084 (1084), 141-149

QSRR approach in examining selected azo dyes
Journal Article

Azo dyes as the most numerous and widely applied class of synthetic dyes in various industries at the same Azo dyes as the most numerous and widely applied class of synthetic dyes in various industries at the same time represent the great polluter of the aquatic systems and environment. Most of them are hydrophobic and resistant to degradation, but also they express diverse biological activity. The preliminary examinations of the bioactivity of the compounds include the estimation of their lipophilicity. The lipophilicity, as the key molecular descriptor for assuming an activity in a biological system for group of thiouracil azo dyes, was determined by the reversed-phase thin-layer chromatography (RPTLC18F254s) in different mixtures of water and (ethanol, i-propanol, dioxane, tetrahydrofurane) and mathematically using relevant software packages. The insight into the relationship between the chromatographic retention parameters, R0m and m of azo dyes with the partition coefficient log P, was attained by applying the linear regression analysis, Cluster analysis, and principal component analysis. All the applied methods have resulted in good agreements of the studied lipophilicity parameters of azo dyes. Also, these methods provided significant informations about the influence of the organic modifier on one side as well as the impact of the polarity and the electronic effect of substituent of examined dyes on their lipophilicity.

Gyöngyi Vastag, Suzana Apostolov, Borko Matijević, Fathi Assaleh, (10-2016), Journal of Liquid Chromatography & Related Technologies: Taylor & Francis Group, 39 (14), 674-681

Solvatochromism of Thiouracil Azo Dyes
Journal Article

A series of sixteen synthesized thiouracil azo dyes was obtained by condensation of arylazo acetoacetic esters with thiourea. Purified products were characterized by UV–Vis, FT–IR, 1H and 13C NMR spectroscopy. The UV–Vis absorption spectra of all synthesized compounds were recorded in nineteen solvents of different properties. The study and analysis of the spectral data of azo dyes generally indicate that the tautomeric equilibrium is shifted to the hydrazone tautomeric form in the solid state. Linear solvation energy relationships describe solvent influence on solvatochromism of the hydrazone form with the use of the Catalán model. Linear free energy relationships were applied in the form of single substituent parameter model to analyze substituent electronic effects on the spectral behavior of the compounds by Hammett’s equation. The correlations obtained with aid of theoretical calculations give insight into the influence of molecular conformation on the transmission of substituent effects, as well as different solvent–solute interactions.

Borko M. Matijević, Đenđi Đ. Vaštag, Suzana Lj. Apostolov, Fathi Assaleh, Aleksandar D. Marinković, Dušan Ž. Mijin, (05-2016), Journal of Solution Chemistry: Springer Nature, 45 (6), 885-906

A LFER Kinetic Study of The Reaction of 5-Substituted Orotic Acids with Diazodiphenylmethane
Journal Article

Linear free energy relationships (LFER) were applied to the kinetic data for the reaction of 5-substituted orotic acids, series 1, with diazodiphenylmethane (DDM) in N,N– dimethylformamide and compared with results obtained for 2-substituted benzoic acids, series 2. The correlation analysis of the kinetic data with σ substituent parameters was carried out using SSP (single substituent parameter) methods. From the sign and value of proportinality constant ρ, lower sensitivity to the substituent effect was obtained in series 1, 0.876, than in the series 2, 1.877. Evaluation of substituent “ortho-effect” was performed using the Charton model, which includes the steric substituent parameter, and Fujita and Nishioka’s model, which describes the total ortho-effect as contribution of ordinary polar effect, the ortho-steric and ortho-polar effects. Results of correlations, obtained by using the Charton model, showed highest contribution of the polar effect, 0.861 vs. 2.101, whereas the steric effect is of lowest significance, 0.117 vs. 0.055, for series and 2, respectively. Also, a low negative value of coefficient with the steric effect, –0.08, obtained from the Fujita–Nishioka model indicated low steric effect, influencing a decrease of the reaction rate in series 1. The structural and substituent effects were also studied by using the density functional theory method, and together with kinetic data, it gave a better insight into the influence of the effect of both geometry and substituent on the π−electron density shift induced reactivity of investigated acids.

Fathi H. Assaleh, Aleksandar D. Marinković, Jasmina B. Nikolić, Saša Ž. Drmanić, Danijela Brković, Nevena Prlainović, Bratislav Ž. Jovanović, (04-2016), International Journal of Chemical Kinetics: Wiley, 48 (7), 367-378

Studying of physicochemical properties of newly synthesized uracil derivatives
Journal Article

Uracil derivatives are potentially biologically active compounds, so the investigation of their physical and chemical properties is very important for their further application. In this work a series of newly synthesized derivatives of uracile was investigated by applying the spectrophotometric method. The absorption spectra were recorded in seventeen solvents with different properties. The effect of solvent was interpreted by Kamlet-Taft solvatochromic model. The dominance and the types of interactions that occur between the investigated derivatives and solvent were interpreted by applying the multiple linear correlation obtained values of absorption maxima and Hansen’s solvent parameters. In addition to the effect of solvent, the influence of substituents in the molecule on absorption spectra was studied by applying Hammett equation.

Borko M. Matijević, Đenđi Đ. Vaštag, Suzana Lj. Apostolov, Jadranka A. Tot, Fathi Assaleh, Aleksandar D. Marinković, (04-2015), Materials protection: Zastita Materijala, 56 (3), 279-288