Insights on cyclophosphamide metabolism and anticancer mechanism of action: A computational study.

The oxazaphosphorine cyclophosphamide (CP) is a DNA-alkylating agent commonly used in cancer chemotherapy. This anticancer agent is administered as a prodrug activated by a liver cytochrome P450-catalyzed 4-hydroxylation reaction that yields the active, cytotoxic metabolite. The primary metabolite, 4-hydroxycyclophosphamide, equilibrates with the ring-open aldophosphamide that undergoes ß-elimination to yield the therapeutically active DNA cross-linking phosphoramide mustard and the byproduct acrolein. The present paper presents a DFT investigation of the different metabolic phases and an insight into the mechanism by which CP exerts its cytotoxic action. A detailed computational analysis of the energy profiles describing all the involved transformations and the mechanism of DNA alkylation is given with the aim to contribute to an increase of knowledge that, after more than 60 years of unsuccessful attempts, can lead to the design and development of a new generation of oxazaphosphorines.

Laburnicolamine: A Rare Penillic Acid Congener from the Nematode Cyst-Associated Fungus Laburnicola nematophila.

A chemical investigation of a methanol extract derived from a solid-state rice culture of the nematode-cyst associated fungus Laburnicola nematophila K01 led to the isolation and characterization of a previously undescribed penillic acid analogue named laburnicolamine (1). The chemical structure was elucidated through comprehensive 1D and 2D NMR spectroscopic analyses in methanol-d4 and DMSO-d6, alongside with HR-ESI-MS spectrometry. The absolute configuration of 1 was concluded through the electronic circular dichroism (ECD) and time-dependent density functional theory-ECD (TDDFT-ECD) computations compared to its acquired spectrum. Biological assays revealed that compound 1 exhibited no significant cytotoxic, antimicrobial, or nematicidal activity.

Dentifragilones A-B and Other Benzoic Acid Derivatives from the European Basidiomycete Dentipellis fragilis.

A chemical and biological exploration of the European polypore Dentipellis fragilis afforded two previously undescribed natural products (1 and 2), together with three known derivatives (3-5). Chemical structures of the isolated compounds were confirmed through 1D/2D NMR spectroscopic analyses, mass spectrometry, and by comparison with the reported literature. The relative and absolute configurations of 1 were determined according to the ROESY spectrum and time-dependent density functional theory electronic circular dichroism (TDDFT-ECD), respectively. Furthermore, the absolute configuration of dentipellinol (3) was revisited and revealed to be of (R) configuration. All the isolated compounds were assessed for their cytotoxic and antimicrobial activities, with some being revealed to have weak to moderate antimicrobial activity, particularly against Gram-positive bacteria.

Exploring the composition of protein-ligand binding sites for cancerous inhibitor of PP2A (CIP2A) by inhibitor guided binding analysis: paving a new way for the Discovery of drug candidates against triple negative breast cancer (TNBC).

Triple-negative breast cancer (TNBC) is associated with high-grade invasive carcinoma leading to a 10% to 15% death rate in younger premenopausal women. Targeting cancerous inhibitors of protein phosphatase (CIP2A) has been a highly effective approach for exploring therapeutic drug candidates. Lapatinib, a dual tyrosine kinase inhibitor, has shown promising inhibition properties by inducing apoptosis in TNBC carcinogenesis in vivo. Despite knowledge of the 3D structure of CIP2A, no reports provide insight into CIP2A ligand binding sites. To this effect, we conducted in silico site identification guided by lapatinib binding. Four of the five sites identified were cross-validated, and the stem domain revealed more excellent ligand binding affinity. The binding affinity of lapatinib in these sites was further computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) approach. According to MM/PBSA//200 ns MD simulations, lapatinib exhibited a higher binding affinity against CIP2A in site 2 with ΔG critical values of -37.1 kcal/mol. The steadiness and tightness of lapatinib with CIP2A inside the stem domain disclosed glutamic acid-318 as the culprit amino acid with the highest electrostatic energy. These results provide clear information on the CIP2A domain capable of ligand binding and validate lapatinib as a promising CIP2A inhibitor in TNBC carcinogenesis.

In Silico Mining of Natural Products Atlas (NPAtlas) Database for Identifying Effective Bcl-2 Inhibitors: Molecular Docking, Molecular Dynamics, and Pharmacokinetics Characteristics.

The Bcl-2 protein has a vital function in controlling the programmed cell doom of mitochondria. If programmed cell death signals are obstructed, an imbalance between cell survival and death will occur, which is a significant reason for cancer. Therefore, the Bcl-2 protein was identified as a possible therapeutic target for carcinoma treatment. Herein, the Natural Products Atlas (NPAtlas) compounds were virtually screened, seeking potent inhibitors towards the Bcl-2 protein. The performance of AutoDock Vina software to predict the docking score and pose of the investigated compounds was first validated according to the available experimental data. Based on the validated AutoDock Vina parameters, the NPAtlas database was filtered against the Bcl-2 protein. The natural compounds with docking scores less than that of the venetoclax (calc. -10.6 kcal/mol) were submitted to MD simulations, followed by MM-GBSA binding energy calculations. According to MM-GBSA//200 ns MD simulations, saquayamycin F (NPA002200) demonstrated promising binding affinity with a ΔGbinding value of -53.9 kcal/mol towards the Bcl-2 protein when compared to venetoclax (ΔGbinding = -50.6 kcal/mol). The energetical and structural analyses showed a great constancy of the saquayamycin F inside the Bcl-2 protein active site. Moreover, the ADMET and drug-likeness features of the saquayamycin F were anticipated, indicating its good oral bioavailability. According to in silico computations, saquayamycin F is proposed to be used as a therapeutic agent against the wild-type Bcl-2 protein and warrants further experimental assays.

Anti-Cancer Peptides: Status and Future Prospects.

The dramatic rise in cancer incidence, alongside treatment deficiencies, has elevated cancer to the second-leading cause of death globally. The increasing morbidity and mortality of this disease can be traced back to a number of causes, including treatment-related side effects, drug resistance, inadequate curative treatment and tumor relapse. Recently, anti-cancer bioactive peptides (ACPs) have emerged as a potential therapeutic choice within the pharmaceutical arsenal due to their high penetration, specificity and fewer side effects. In this contribution, we present a general overview of the literature concerning the conformational structures, modes of action and membrane interaction mechanisms of ACPs, as well as provide recent examples of their successful employment as targeting ligands in cancer treatment. The use of ACPs as a diagnostic tool is summarized, and their advantages in these applications are highlighted. This review expounds on the main approaches for peptide synthesis along with their reconstruction and modification needed to enhance their therapeutic effect. Computational approaches that could predict therapeutic efficacy and suggest ACP candidates for experimental studies are discussed. Future research prospects in this rapidly expanding area are also offered.

Adsorption Features of Tetrahalomethanes (CX4; X = F, Cl, and Br) on ß12 Borophene and Pristine Graphene Nanosheets: A Comparative DFT Study.

The potentiality of the ß12 borophene (ß12) and pristine graphene (GN) nanosheets to adsorb tetrahalomethanes (CX4; X = F, Cl, and Br) were investigated using density functional theory (DFT) methods. To provide a thorough understanding of the adsorption process, tetrel (XC-X3∙∙∙ß12/GN)- and halogen (X3C-X∙∙∙ß12/GN)-oriented configurations were characterized at various adsorption sites. According to the energetic manifestations, the adsorption process of the CX4∙∙∙ß12/GN complexes within the tetrel-oriented configuration led to more desirable negative adsorption energy (Eads) values than that within the halogen-oriented analogs. Numerically, Eads values of the CBr4∙∙∙Br1@ß12 and T@GN complexes within tetrel-/halogen-oriented configurations were -12.33/-8.91 and -10.03/-6.00 kcal/mol, respectively. Frontier molecular orbital (FMO) results exhibited changes in the EHOMO, ELUMO, and Egap values of the pure ß12 and GN nanosheets following the adsorption of CX4 molecules. Bader charge transfer findings outlined the electron-donating property for the CX4 molecules after adsorbing on the ß12 and GN nanosheets within the two modeled configurations, except the adsorbed CBr4 molecule on the GN sheet within the tetrel-oriented configuration. Following the adsorption process, new bands and peaks were observed in the band structure and density of state (DOS) plots, respectively, with a larger number in the case of the tetrel-oriented configuration than in the halogen-oriented one. According to the solvent effect affirmations, adsorption energies of the CX4∙∙∙ß12/GN complexes increased in the presence of a water medium. The results of this study will serve as a focal point for experimentalists to better comprehend the adsorption behavior of ß12 and GN nanosheets toward small toxic molecules.

The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)'s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19.

The unusual and interesting architecture of the catalytic chamber of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) was recently explored using Cryogenic Electron Microscopy (Cryo-EM), which revealed the presence of two distinctive binding cavities within the catalytic chamber. In this report, first, we mapped out and fully characterized the variations between the two binding sites, BS1 and BS2, for significant differences in their amino acid architecture, size, volume, and hydrophobicity. This was followed by investigating the preferential binding of eight antiviral agents to each of the two binding sites, BS1 and BS2, to understand the fundamental factors that govern the preferential binding of each drug to each binding site. Results showed that, in general, hydrophobic drugs, such as remdesivir and sofosbuvir, bind better to both binding sites than relatively less hydrophobic drugs, such as alovudine, molnupiravir, zidovudine, favilavir, and ribavirin. However, suramin, which is a highly hydrophobic drug, unexpectedly showed overall weaker binding affinities in both binding sites when compared to other drugs. This unexpected observation may be attributed to its high binding solvation energy, which disfavors overall binding of suramin in both binding sites. On the other hand, hydrophobic drugs displayed higher binding affinities towards BS1 due to its higher hydrophobic architecture when compared to BS2, while less hydrophobic drugs did not show a significant difference in binding affinities in both binding sites. Analysis of binding energy contributions revealed that the most favorable components are the ΔEele, ΔEvdw, and ΔGgas, whereas ΔGsol was unfavorable. The ΔEele and ΔGgas for hydrophobic drugs were enough to balance the unfavorable ΔGsol, leaving the ΔEvdw to be the most determining factor of the total binding energy. The information presented in this report will provide guidelines for tailoring SARS-CoV-2 inhibitors with enhanced binding profiles.

Feature-Based Molecular Networking for the Exploration of the Metabolome Diversity of Common Egyptian Centaurea Species in Relation to Their Cytotoxic Activity.

Centaurea is a genus compromising over 250 herbaceous flowering species and is used traditionally to treat several ailments. Among the Egyptian Centaurea species, C. lipii was reported to be cytotoxic against multidrug-resistant cancer cells. In this context, we aimed to explore the metabolome of C. lipii and compare it to other members of the genus in pursuance of identifying its bioactive principles. An LC-MS/MS analysis approach synchronized with feature-based molecular networks was adopted to offer a holistic overview of the metabolome diversity of the Egyptian Centaurea species. The studied plants included C. alexandrina, C. calcitrapa, C. eryngioides, C. glomerata, C. lipii, C. pallescens, C. pumilio, and C. scoparia. Their constitutive metabolome showed diverse chemical classes such as cinnamic acids, sesquiterpene lactones, flavonoids, and lignans. Linking the recorded metabolome to the previously reported cytotoxicity identified sesquiterpene lactones as the major contributors to this activity. To confirm our findings, bioassay-guided fractionation of C. lipii was adopted and led to the isolation of the sesquiterpene lactone cynaropicrin with an IC50 of 1.817 µM against the CCRF-CEM leukemia cell line. The adopted methodology highlighted the uniqueness of the constitutive metabolome of C. lipii and determined the sesquiterpene lactones to be the responsible cytotoxic metabolites.

Pyronaridine as a Bromodomain-Containing Protein 4-N-Terminal Bromodomain (BRD4-BD1) Inhibitor: In Silico Database Mining, Molecular Docking, and Molecular Dynamics Simulation.

BRD4 (bromodomain-containing protein 4) is an epigenetic reader that realizes histone proteins and promotes the transcription of genes linked to cancer progression and non-cancer diseases such as acute heart failure and severe inflammation. The highly conserved N-terminal bromodomain (BD1) recognizes acylated lysine residues to organize the expression of genes. As such, BD1 is essential for disrupting BRD4 interactions and is a promising target for cancer treatment. To identify new BD1 inhibitors, a SuperDRUG2 database that contains more than 4600 pharmaceutical compounds was screened using in silico techniques. The efficiency of the AutoDock Vina1.1.2 software to anticipate inhibitor-BRD4-BD1 binding poses was first evaluated based on the co-crystallized R6S ligand in complex with BRD4-BD1. From database screening, the most promising BRD4-BD1 inhibitors were subsequently submitted to molecular dynamics (MD) simulations integrated with an MM-GBSA approach. MM-GBSA computations indicated promising BD1 binding with a benzonaphthyridine derivative, pyronaridine (SD003509), with an energy prediction (ΔGbinding) of -42.7 kcal/mol in comparison with -41.5 kcal/mol for a positive control inhibitor (R6S). Pharmacokinetic properties predicted oral bioavailability for both ligands, while post-dynamic analyses of the BRD4-BD1 binding pocket demonstrated greater stability for pyronaridine. These results confirm that in silico studies can provide insight into novel protein-ligand regulators, specifically that pyronaridine is a potential cancer drug candidate.

Unusual chalcogen⋯chalcogen interactions in like⋯like and unlike YCY⋯YCY complexes (Y = O, S, and Se).

Chalcogen⋯chalcogen interactions were investigated within four types of like⋯like and unlike YCY⋯YCY complexes (where Y = O, S, or Se). A plethora of quantum mechanical calculations, including molecular electrostatic potential (MEP), surface electrostatic potential extrema, point-of-charge (PoC), quantum theory of atoms in molecules (QTAIM), noncovalent interaction (NCI), and symmetry-adapted perturbation theory-based energy decomposition analysis (SAPT-EDA) calculations, were executed. The energetic findings revealed a preferential tendency of the studied chalcogen-bearing molecules to engage in type I, II, III, or IV chalcogen⋯chalcogen interactions. Notably, the selenium-bearing molecules exhibited the most potent ability to favorably participate in all the explored chalcogen⋯chalcogen interactions. Among like⋯like complexes, type IV interactions showed the most favorable negative binding energies, whereas type III interactions exhibited the weakest binding energies. Unexpectedly, oxygen-containing complexes within type IV interactions showed an alien pattern of binding energies that decreased along with an increase in the chalcogen atomic size level. QTAIM analysis provided a solo BCP, via chalcogen⋯chalcogen interactions, with no clues as to any secondary ones. SAPT-EDA outlined the domination of the explored interactions by the dispersion forces and indicated the pivotal shares of the electrostatic forces, except type III σ-hole⋯σ-hole and di-σ-hole interactions. These observations demonstrate in better detail all the types of chalcogen⋯chalcogen interactions, providing persuasive reasons for their more intensive use in versatile fields related to materials science and drug design.

Naturally occurring plant-based anticancerous candidates as prospective ABCG2 inhibitors: an in silico drug discovery study.

ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter related to the clinical multidrug resistance (MDR) phenomenon. Identifying ABCG2 inhibitors could help discover extraordinary curative strategies for carcinoma remediation. Hitherto, there is no medication drug inhibiting ABCG2 transporter, notwithstanding that a considerable number of drugs have been submitted to clinical-trial and investigational phases. In the search for unprecedented chemical compounds that could inhibit the ABCG2 transporter, an in silico screening was conducted on the Naturally Occurring Plant-based Anticancer Compound-Activity-Target (NPACT) database containing 1574 compounds. Inhibitor-ABCG2 binding affinities were estimated based on molecular docking and molecular minimization (MM) calculations and compared to a co-crystallized inhibitor (BWQ) acting as a reference inhibitor. Molecular dynamics (MD) simulations pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations were further executed for compounds with MM-GBSA//MM binding energies lower than BWQ (calc. - 60.5 kcal/mol). NPACT00968 and NPACT01545 demonstrated auspicious inhibitory activities according to binding affinities (ΔGbinding) over the 100 ns MD simulations that were nearly one and a half folds compared to BWQ (- 100.4, - 94.7, and - 62.9 kcal/mol, respectively). Throughout the 100 ns MD simulations, structural and energetical analyses unveiled outstanding stability of the ABCG2 transporter when bound with NPACT00968 and NPACT01545. In silico calculations hold a promise for those two inhibitors as drug candidates of ABCG2 transporter and emphasize that further in vitro and in vivo experiments are guaranteed.

Synthesis, X-ray diffraction analysis, quantum chemical studies and α-amylase inhibition of probenecid derived S-alkylphthalimide-oxadiazole-benzenesulfonamide hybrids.

Sulphonamide and 1,3,4-oxadiazole moieties are present as integral structural parts of many drugs and pharmaceuticals. Taking into account the significance of these moieties, we herein present the synthesis, single-crystal X-ray analysis, DFT studies, and α-amylase inhibition of probenecid derived two S-alkylphthalimide-oxadiazole-benzenesulfonamide hybrids. The synthesis has been accomplished in high yields. The final structures of both hybrids have been established completely with the help of different spectro-analytical techniques, including NMR, FTIR, HR-MS, and single-crystal X-ray diffraction analyses. In an effort to confirm the experimental findings, versatile quantum mechanical calculations and Hirshfeld Surface analysis have been performed. α-Amylase inhibition assay has been executed to investigate the enzyme inhibitory potential of both hybrids. The low IC50 value (76.92 ± 0.19 µg/mL) of hybrid 2 shows the good α-amylase inhibition potential of the respective compound. Ultimately, the binding affinities and features of the two hybrids are elucidated utilising a molecular docking technique against the α-amylase enzyme.

Type I-IV Halogen⋯Halogen Interactions: A Comparative Theoretical Study in Halobenzene⋯Halobenzene Homodimers.

In the current study, unexplored type IV halogen⋯halogen interaction was thoroughly elucidated, for the first time, and compared to the well-established types I−III interactions by means of the second-order Møller−Plesset (MP2) method. For this aim, the halobenzene⋯halobenzene homodimers (where halogen = Cl, Br, and I) were designed into four different types, parodying the considered interactions. From the energetic perspective, the preference of scouted homodimers was ascribed to type II interactions (i.e., highest binding energy), whereas the lowest binding energies were discerned in type III interactions. Generally, binding energies of the studied interactions were observed to decline with the decrease in the σ-hole size in the order, C6H5I⋯IC6H5 > C6H5Br⋯BrC6H5 > C6H5Cl⋯ClC6H5 homodimers and the reverse was noticed in the case of type IV interactions. Such peculiar observations were relevant to the ample contributions of negative-belt⋯negative-belt interactions within the C6H5Cl⋯ClC6H5 homodimer. Further, type IV torsional trans → cis interconversion of C6H5X⋯XC6H5 homodimers was investigated to quantify the π⋯π contributions into the total binding energies. Evidently, the energetic features illustrated the amelioration of the considered homodimers (i.e., more negative binding energy) along the prolonged scope of torsional trans → cis interconversion. In turn, these findings outlined the efficiency of the cis configuration over the trans analog. Generally, symmetry-adapted perturbation theory-based energy decomposition analysis (SAPT-EDA) demonstrated the predominance of all the scouted homodimers by the dispersion forces. The obtained results would be beneficial for the omnipresent studies relevant to the applications of halogen bonds in the fields of materials science and crystal engineering.

Effects of Lewis Basicity and Acidity on σ-Hole Interactions in Carbon-Bearing Complexes: A Comparative Ab Initio Study.

The effects of Lewis basicity and acidity on σ-hole interactions were investigated using two sets of carbon-containing complexes. In Set I, the effect of Lewis basicity was studied by substituting the X3/X atom(s) of the NC-C6H2-X3 and NCX Lewis bases (LB) with F, Cl, Br, or I. In Set II, the W-C-F3 and F-C-X3 (where X and W = F, Cl, Br, and I) molecules were utilized as Lewis acid (LA) centers. Concerning the Lewis basicity effect, higher negative interaction energies (Eint) were observed for the F-C-F3∙∙∙NC-C6H2-X3 complexes compared with the F-C-F3∙∙∙NCX analogs. Moreover, significant Eint was recorded for Set I complexes, along with decreasing the electron-withdrawing power of the X3/X atom(s). Among Set I complexes, the highest negative Eint was ascribed to the F-C-F3∙∙∙NC-C6H2-I3 complex with a value of -1.23 kcal/mol. For Set II complexes, Eint values of F-C-X3 bearing complexes were noted within the -1.05 to -2.08 kcal/mol scope, while they ranged from -0.82 to -1.20 kcal/mol for the W-C-F3 analogs. However, Vs,max quantities exhibited higher values in the case of W-C-F3 molecules compared with F-C-X3; preferable negative Eint were ascribed to the F-C-X3 bearing complexes. These findings were delineated as a consequence of the promoted contributions of the X3 substituents. Dispersion forces (Edisp) were identified as the dominant forces for these interactions. The obtained results provide a foundation for fields such as crystal engineering and supramolecular chemistry studies that focus on understanding the characteristics of carbon-bearing complexes.

Autoxidation of 4-Hydrazinylquinolin-2(1H)-one; Synthesis of Pyridazino[4,3-c:5,6-c']diquinoline-6,7(5H,8H)-diones.

An efficient synthesis of a series of pyridazino[4,3-c:5,6-c']diquinolines was achieved via the autoxidation of 4-hydrazinylquinolin-2(1H)-ones. IR, NMR (1H and 13C), mass spectral data, and elemental analysis were used to fit and elucidate the structures of the newly synthesized compounds. X-ray structure analysis and theoretical calculations unequivocally proved the formation of the structure. The possible mechanism for the reaction is also discussed.

Interactions of Apigenin and Safranal with the 5HT1A and 5HT2A Receptors and Behavioral Effects in Depression and Anxiety: A Molecular Docking, Lipid-Mediated Molecular Dynamics, and In Vivo Analysis.

BACKGROUND: The current study utilizes in silico molecular docking/molecular dynamics to evaluate the binding affinity of apigenin and safranal with 5HT1AR/5HT2AR, followed by assessment of in vivo effects of these compounds on depressive and anxious behavior. METHODS: The docking between apigenin and safranal and the 5HT1A and 5HT2A receptors was performed utilizing AutoDock Vina software, while MD and protein-lipid molecular dynamics simulations were executed by AMBER16 software. For in vivo analysis, healthy control (HC), disease control (DC), fluoxetine-, and apigenin-safranal-treated rats were tested for changes in depression and anxiety using the forced swim test (FST) and the elevated plus-maze test (EPMT), respectively. RESULTS: The binding affinity estimations identified the superior interacting capacity of apigenin over safranal for 5HT1A/5HT2A receptors over 200 ns MD simulations. Both compounds exhibit oral bioavailability and absorbance. In the rodent model, there was a significant increase in the overall mobility time in the FST, while in the EPMT, there was a decrease in latency and an increase in the number of entries for the treated and HC rats compared with the DC rats, suggesting a reduction in depressive/anxiety symptoms after treatment. CONCLUSIONS: Our analyses suggest apigenin and safranal as prospective medication options to treat depression and anxiety.

Exploring Natural Product Activity and Species Source Candidates for Hunting ABCB1 Transporter Inhibitors: An In Silico Drug Discovery Study.

The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ΔGbinding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.

External Electric Field Effect on the Strength of σ-Hole Interactions: A Theoretical Perspective in Like⋯Like Carbon-Containing Complexes.

For the first time, σ-hole interactions within like⋯like carbon-containing complexes were investigated, in both the absence and presence of the external electric field (EEF). The effects of the directionality and strength of the utilized EEF were thoroughly unveiled in the (F-C-F3)2, (F-C-H3)2, and (H-C-F3)2 complexes. In the absence of the EEF, favorable interaction energies, with negative values, are denoted for the (F-C-F3)2 and (H-C-F3)2 complexes, whereas the (F-C-H3)2 complex exhibits unfavorable interactions. Remarkably, the strength of the applied EEF exhibits a prominent role in turning the repulsive forces within the latter complex into attractive ones. The symmetrical nature of the considered like⋯like carbon-containing complexes eradicated the effect of directionality of the EEF. The quantum theory of atoms in molecules (QTAIM), and the noncovalent interaction (NCI) index, ensured the occurrence of the attractive forces, and also outlined the substantial contributions of the three coplanar atoms to the total strength of the studied complexes. Symmetry-adapted perturbation theory (SAPT) results show the dispersion-driven nature of the interactions.

Synthesis of 3,3'-methylenebis(4-hydroxyquinolin-2(1H)-ones) of prospective anti-COVID-19 drugs.

During formylation of 2-quinolones by DMF/Et3N mixture, the unexpected 3,3'-methylenebis(4-hydroxyquinolin-2(1H)-ones) were formed. The discussed mechanism was proved as due to the formation of 4-formyl-2-quinolone as intermediate. Reaction of the latter compound with the parent quinolone under the same reaction condition gave also the same product. The structure of the obtained products was elucidated via NMR, IR and mass spectra. X-ray structure analysis proved the anti-form of the obtained compounds, which were stabilized by the formation hydrogen bond. Molecular docking calculations showed that most of the synthesized compounds possessed good binding affinity to the SARS-CoV-2 main protease (Mpro) in comparable to Darunavir.