In this study, we explored the potential of novel$N$protocatechoyl hydrazone derivatives as inhibitors of epidermal growth factor receptor (EGFR) kinase, a key target in cancer therapy. Using the CReM webserver, we generated 100 unique derivatives starting from compound L, all of which displayed favorable synthetic accessibility and drug-like characteristics as proven by ADME screening (with a LogP value of less than 3). Out of these, 34 compounds satisfied the Lipinski Rule of Five and were further examined for their ability to bind to EGFR using molecular docking simulations and a deep learning algorithm. Nine compounds demonstrated binding energies below –41.2 kJ/mol, surpassing the reference inhibitor Mavelertinib (MAV, –38.5 kJ/mol), and indicating their greater potential for inhibiting EGFR. The molecular docking analysis showed that the interactions were facilitated by specific amino acids such as MET793 and THR854, as well as different noncovalent forces including hydrogen bonds and$\pi-\pi$interactions. Analysis using the ProToxIII website revealed that out of the nine most promising compounds, only two, L and L1, exhibited lower anticipated toxicity than MAV. Among these, L had the biggest safety margin, with an$\text{LD}_{50}$value of 5000 mg/kg. Based on these findings, compounds L and L1 have been identified as the most promising candidates for further in vitro testing as potential anticancer drugs.

In this study, in vitro and in silico interactions of bovine serum albumin with chromeno-pyrimidine derivatives (CP), 5-(7- bromo-2,4-dioxo-1,3,4,5-tetrahydro-2H-chromeno-[2,3-d]pyrimidin-5-yl)pyrimidine2,4,6(1H,3H,5H)-tri-one (CP1) and 8,9-dihydroxy-2H-chromeno[2,3-d] pyrimidine$2,4(3 H)$dione (CP-2), are investigated. The high value of in vitro obtained binding constants are the result of good binding of the investigated compounds to BSA. Molecular docking results explain the interactions of BSA to the tested compounds and it is consistent with the experimentally obtained results.

Carbonic anhydrase isoforms IX and XII are crucial for the regulation of extracellular pH thus facilitating cancer cell proliferation, invasion, and metastasis. Therefore, discovering good inhibitors of CA-IX and CA-XII is of great importance. In this study, the inhibitory activity of previously synthesized coumarin-hydroxybenzohydrazide 3a and its parent molecule 4-hydroxycoumarin, against enzymes CA-IX and CA-XII was investigated. For that purpose, the molecular docking study was performed. The activity of both investigated compounds was calculated for neutral and anionic species. The obtained results indicate that compound 3a expresses good inhibitory activity towards both investigated enzymes, but inhibitory activity is significantly better towards CA-XII than CA-IX.

In this contribution are estimated and compared free radical scavenger capacity of 1,2,5- trihydroxyanthraquinone (AN) and 1,2,5-trihydroxythioxanthone (TX). For this purpose,$\mathbf{M06}-\mathbf{2X/6}-311++\mathbf{G}(\mathbf{d, p})$method is used. Scavenger capacities of both molecules are determined in benzene and water. It is found that both antioxidants generate stable radicals in water following SPLET mechanism. On the other hand, the most plausible mechanism for that purpose in benzene is HAT. In the presence of three selected free radicals$(\mathbf{HO}^{\bullet},\mathbf{HOO}^{\bullet}\mathbf{and}\ \mathbf{CH_{3}OO}^{\bullet})$these molecules manifest their scavenger capacity following HAT and SPLET competitively in both estimated environment conditions. The reactivity of observed molecules toward free radicals decreases following the order:$\mathbf{HO}^{\bullet}\gg\mathbf{HOO}^{\bullet}>\mathbf{CH_{3}OO}^{\bullet}$. Comparing thermodynamic parameters that describe homolytic O-H cleavage for estimated antioxidants, it is concluded that TX shows somewhat higher scavenger capacity.

Heart failure (HF) is a condition that affects mostly older populations. It can be treated with different medications, and one of them is Entresto. This is a medication which is consisting of two drugs, sacubitril (SAC) and valsartan (VAL). Here, in this study, are performed molecular docking simulations in order to examine the inhibitory potency of SAC and VAL towards neprilysin (NEP) and angiotensin II receptor (AT2), respectively. The achieved thermodynamic parameters shows that SAC and VAL can bind to targeted protein, and inhibit NEP and AT2. The best binding sites are determined. Also, the amino acids responsible for binding are identified.

Different phenolic coumarin derivatives represent a widespread class of compounds that have shown remarkable activity in removing reactive oxygen species. For this reason, within this study, the antiradical activity of previously synthesized phenolic derivatives of 4,7 -dihydroxycoumarin: (E)-3-(1-((2-hydroxyphenyl)amino) ethylidene) -2,4-dioxochroman-7-yl (A-20H),$(E)$-3-(1((3-hydroxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A-30H),$(E)$. -3-(1((4-hydroxyphenyl)amino) ethylidene) -2,4-dioxochroman-7-yl (A-40H) acetate against the 2,2-diphenyl-1-picrylhydrazyl (DPPH·) radical was investigated. All research is supported by Density Functional Theory$(\mathbf{DFT}/\mathbf{M06}-\mathbf{2X/6-311++}\mathbf{G}(\mathbf{d, p})$level of theory and CPCM solvation model-methanol) in combination with global chemical reactivity parameters. The results of experimental scavenging activity towards DPPH· indicate that A-20H shows the best activity. The most probable scavenging route was determined based on the thermodynamic parameters. A good correlation between experiment and theory showed that Hydrogen Atom Transfer (HAT,$\Delta\text{rGHAT}$) was the dominant pathway of the reduction of DPPH·. In general, the results of global chemical reactivity parameters show that the A-40H compound shows the best electron-donating properties, which is correlated with thermodynamic parameters obtained for the Single Electron Transfer (SET,$\Delta{\text{rGSET}}$) mechanism.

The isonicotinohydrazide moiety is a common structural motif of the biologically active compounds with pronounced therapeutic effects. Four isonicotinohydrazide analogs were investigated to elucidate the importance of various substituents on the predicted biological activity. The structures of these compounds were optimized at the M06-2X16-311++G(d, p) level of theory based on the crystallographic structures. The intermolecular interactions governing the stability of these compounds were analyzed by the Natural Bond Orbital theory. The molecular docking studies towards Cyclin-Dependent Kinase 2 (CDK2) were performed and the specific interactions of present substituents were described. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of these compounds were predicted by the SWISSADME and Prediction of Toxicity (ProTox-II) webservers. The ecotoxicity study also showed that these compounds might be potentially toxic towards fish, daphnia, and green algae. The similarity in toxicity and reactivity of these compounds is a consequence of the present substituents.

The antioxidant activity of evernic acid acid was studied in the absence and in the present of free radical species. This in silico study was performed in water solvent, to mimic polar environment. The reaction enthalpies for reactions of evernic acid with three different free radicals are presented. The molecular docking study was performed in order to estimate the inhibition activity of investigated compound toward Human tyrosine-DNA phosphodiesterase (TDP1). The obtained results indicate that a numerous interactions determine the activity towards investigated protein. In addition, molecular dynamic simulation were done.

Free radical scavenging of gallic acid was studied through electron transfer mechanism (ET) in water and pentylethanoate solutions. Examination was performed using density functional theory (DFT) and Marcus theory. Three particular free radicals were selected for analysis of mechanistic pathway of the second step of sequential proton loss electron transfer (SPLET). Based on the thermochemical and kinetic data, it is presumed which hydroxyl group of gallic acid is more suitable for reaction through mentioned antioxidant mechanism. Obtained results are in line with our previous reports.

Alizarin is anthraquinone with moderate antioxidative capacity. In this work mechanisms of antioxidative activity of alizarin with hydroperoxy and methylperoxy radicals are investigated. All calculations are carried out using B3LYP-D2 method and 6–311+G(d, p) basis set. It is affirmed based on several parameters that hydroxyl group at position 2 is predominant for antiradical activity. PCET mechanism is estimated as favorable mechanism for scavenging activity of alizarin with two selected radicals.

Cyanidin, as one important plant pigment, was theoretically (at M05-2X/6-311+G(d, p) level of theory) investigated for its ability to scavenge potentially, highly damaging hydroxyl radical. The applied method successfully reproduces the bond dissociation enthalpy (BDE), the ionization potential (IP) and proton affinity (PA). The HAT mechanism is most favorable reaction pathway for antioxidative action of cyanidin in the gas phase. On the other hand, the SPLET mechanism is most favorable reaction pathway for antioxidative action of cyanidin in the aqueous phase. Mechanistic investigations of antioxidative action of cyanidin in reaction with the hydroxyl radical confirmed that HAT is the dominant reaction pathway in the gas phase, and that the 4' position is most reactive.