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Candida albicans and Aspergillus fumigatus are recognized as significant fungal pathogens, responsible for various human infections. The rapid emergence of drug-resistant strains among these fungi requires the identification and development of innovative antifungal therapies. We undertook a comprehensive screening of 297 naturally occurring compounds to address this challenge. Using computational docking techniques, we systematically analyzed the binding affinity of each compound to key proteins from Candida albicans (PDB ID: 1EAG) and Aspergillus fumigatus (PDB ID: 3DJE). This rigorous in silico examination aimed to unveil compounds that could potentially inhibit the activity of these fungal infections. This was followed by an ADMET analysis of the top-ranked compound, providing valuable insights into the pharmacokinetic properties and potential toxicological profiles. To further validate our findings, the molecular reactivity and stability were computed using the DFT calculation and molecular dynamics simulation, providing a deeper understanding of the stability and behavior of the top-ranking compounds in a biological environment. The outcomes of our study identified a subset of natural compounds that, based on our analysis, demonstrate notable potential as antifungal candidates. With further experimental validation, these compounds could pave the way for new therapeutic strategies against drug-resistant fungal pathogens. [ABSTRACT FROM AUTHOR]

Stellatolides are natural compounds that have shown promising biological activities, including antitumor, antimicrobial, and anti-inflammatory properties, making them potential candidates for drug development. Chemical Reactivity Theory (CRT) is a branch of chemistry that explains and predicts the behavior of chemical reactions based on the electronic structure of molecules. Conceptual Density Functional Theory (CDFT) and Computational Peptidology (CP) are computational approaches used to study the behavior of atoms, molecules, and peptides. In this study, we present the results of our investigation of the chemical reactivity and ADMET properties of Stellatolides A-H using a novel computational approach called Conceptual DFT-based Computational Peptidology (CDFT-CP). Our study uses CDFT and CP to predict the reactivity and stability of molecules and to understand the behavior of peptides at the molecular level. We also predict the ADMET properties of the Stellatolides A–H to provide insight into their effectiveness, potential side effects, and optimal dosage and route of administration, as well as their biological targets. This study sheds light on the potential of Stellatolides A–H as promising candidates for drug development and highlights the potential of CDFT-CP for the study of other natural compounds and peptides. [ABSTRACT FROM AUTHOR]

A series of ten new hydrazide–hydrazone derivatives bearing a pyrrole ring were synthesized and structurally elucidated through appropriate spectral characteristics. The target hydrazones were assessed for radical scavenging activity through 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) tests, with ethyl 5-(4-bromophenyl)-1-(2-(2-(4-hydroxy-3,5-dimethoxybenzylidene)hydrazine-yl)-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate (7d) and ethyl 5-(4-bromophenyl)-1-(3-(2-(4-hydroxy-3,5-dimethoxybenzylidene) hydra zine-yl)-3-oxopropyl)-2-methyl-1H-pyrrole-3-carboxylate (8d) highlighted as the best radical scavengers from the series. Additional density functional theory (DFT) studies have indicated that the best radical scavenging ligands in the newly synthesized molecules are stable, do not decompose into elements, are less polarizable, and with a hard nature. The energy of the highest occupied molecular orbital (HOMO) revealed that both compounds possess good electron donation capacities. Overall, 7d and 8d can readily scavenge free radicals in biological systems via the donation of hydrogen atoms and single electron transfer. The performed in vitro assessment of the compound's protective activity on the H2O2-induced oxidative stress model on human neuroblastoma cell line SH-SY5Y determined 7d as the most perspective representative with the lowest cellular toxicity and the highest protection. [ABSTRACT FROM AUTHOR]

1,4−naftoquinone (NQ) molecules have been extensively evaluated as potent antibacterial compounds; however, their use is limited, since they have low water solubility and exhibit toxicities in healthy eukaryotic cells. A possible path to overcoming these challenges is the use of particulate vehicles, such as SBA-15, which is a biocompatible and biodegradable mesoporous silica material, that may enhance drug delivery and decrease dosages. In this work, an isotherm model-based adsorption of three NQs into SBA-15 microparticles was evaluated. Interactions between NQs and SBA-15 microparticles were modeled at the B3LYP/6-31+G(d,p) level of theory to understand the nature of such interactions. The results demonstrated that the adsorption of NQ, 2NQ, and 5NQ into SBA-15 fit the Freundlich adsorption model. According to theorical studies, physisorption is mediated by hydrogen bonds, while the most stable interactions occur between the carbonyl group of NQ and silica surfaces. Both experimental and theoretical results contribute to a deeper understanding of the use of SBA-15 or similar particles as nanovehicles in such a way that NQs can be modified in carbonyl or C3 to enhance adsorptions. The theoretical and experimental results were in accordance and contribute to a deeper understanding of how interactions between NQ-type molecules and SiO2 materials occur. [ABSTRACT FROM AUTHOR]

The preclinical drug discovery stage often requires a large amount of costly and time-consuming experiments using huge sets of chemical compounds. In the last few decades, this process has undergone significant improvements by the introduction of quantitative structure-activity relationship (QSAR) modelling that uses a certain percentage of experimental data to predict the biological activity/property of compounds with similar structural skeleton and/or containing a particular functional group(s). The use of machine learning tools along with it has made life even easier for pharmaceutical researchers. Here, we discuss the toxicity of certain sets of bioactive compounds towards Pimephales promelas and Tetrahymena pyriformis in terms of the global conceptual density functional theory (CDFT)-based descriptor, electrophilicity index (ω). We have compared the results with those obtained by using the commonly used hydrophobicity parameter, logP (where P is the n-octanol/water partition coefficient), considering the greater ease of computing the ω descriptor. The Human African trypanosomiasis (HAT) curing activity of 32 pyridyl benzamide derivatives is also studied against Tryphanosoma brucei. In this review article, we summarize these multiple linear regression (MLR)-based QSAR studies in terms of electrophilicity (ω, ω2) and hydrophobicity (logP, (logP)2) parameters. [ABSTRACT FROM AUTHOR]

The position of conceptual density functional theory (CDFT) in the history of density functional theory (DFT) is sketched followed by a chronological report on the introduction of the various DFT descriptors such as the electronegativity, hardness, softness, Fukui function, local version of softness and hardness, dual descriptor, linear response function, and softness kernel. Through a perturbational approach they can all be characterized as response functions, reflecting the intrinsic reactivity of an atom or molecule upon perturbation by a different system, including recent extensions by external fields. Derived descriptors such as the electrophilicity or generalized philicity, derived from the nature of the energy vs. N behavior, complete this picture. These descriptors can be used as such or in the context of principles such as Sanderson's electronegativity equalization principle, Pearson's hard and soft acids and bases principle, the maximum hardness, and more recently, the minimum electrophilicity principle. CDFT has known an ever-growing use in various subdisciplines of chemistry: from organic to inorganic chemistry, from polymer to materials chemistry, and from catalysis to nanotechnology. The increasing size of the systems under study has been coped with thanks to methodological evolutions but also through the impressive evolution in software and hardware. In this flow, biosystems entered the application portfolio in the past twenty years with studies varying (among others) from enzymatic catalysis to biological activity and/or the toxicity of organic molecules and to computational peptidology. On the basis of this evolution, one can expect that "the best is yet to come". [ABSTRACT FROM AUTHOR]

Non-covalent π-π stacking interactions often play a key role in the stability of the secondary and tertiary structures of peptides and proteins, respectively, and can be a means of ensuring the binding of ligands within protein and enzyme binding sites. It is generally accepted that minor structural changes to the aromatic ring, such as substitution, can have a large influence on these interactions. Nevertheless, a thorough understanding of underpinning phenomena guiding these key interactions is still limited. This is especially true for larger aromatic structures. To expand upon this knowledge, elaborate ab initio calculations were performed to investigate the effect of halogenation on the stability of 3-methylindole stacking. 3-Methylindole served as a representation of the tryptophan side chain, and is a frequently used motif in drug design and development. Moreover, an expression is derived that is able to accurately predict the interaction stability of stacked halogenated 3-methylindole dimers as well as halogenated toluene dimers, based on monomer level calculated DFT descriptors. We aim for this expression to provide the field with a straightforward and reliable method to assess the effect of halogenation on the π-π stacking interactions between aromatic scaffolds. [ABSTRACT FROM AUTHOR]

Using density functional theory (DFT) and the information-theoretic approach (ITA) quantities to appreciate the energetics and properties of biopolymers is still an unaccomplished and ongoing task. To this end, we studied the building blocks of nucleic acid base pairs and small peptides. For base pairs, we have dissected the relative importance of energetic components by using two energy partition schemes in DFT. Our results convincingly show that the exchange-correlation effect predominantly governs the molecular stability of base pairs while the electrostatic potential plays a minor but indispensable role, and the steric effect is trivial. Furthermore, we have revealed that simple density-based ITA functions are in good relationships with molecular polarizabilities for a series of 30 hydrogen-bonded base pairs and all 20 natural α-amino acids, 400 dipeptides, and 8000 tripeptides. Based on these lines, one can easily predict the molecular polarizabilities of larger peptides, even proteins as long as the total molecular wavefunction is available, rather than solving the computationally demanding coupled-perturbed Hartree–Fock (CPHF) equation or its DFT counterpart coupled-perturbed Kohn–Sham (CPKS) equation. [ABSTRACT FROM AUTHOR]

Two novel co-crystals of naproxen (NPX) were designed and prepared at a stoichiometric ratio of 1:1, namely, naproxen–caprolactam (NPX–CPL) and naproxen–oxymatrine (NPX–OMT). The characteristics of the co-crystals were evaluated in terms of stability and solubility studies. In terms of solubility, in four kinds of solvent systems with different pH, the solubility of NPX–OMT was significantly improved compared with that of NPX, whereas the NPX–CPL showed advantages in acidic solvent systems, indicating that the co-crystals can be applied to concoct preparations depending on therapeutic purposes. Furthermore, the experimental results of the thermal analysis showed that the co-crystal NPX–OMT had better thermal stability than the co-crystal NPX–CPL. Finally, as a complement to the single crystal X-ray diffraction (SC XRD) method, the theoretical calculation based on density functional theory (DFT) was also used to reveal the intermolecular interaction of the co-crystals at the molecular level and visually display the difference between them. [ABSTRACT FROM AUTHOR]

Para-sulfocalix[n]arenes are promising host molecules that can accommodate various chemotherapeutic drugs. Pt(IV)-based complexes, including satraplatin and asplatin, are promising alternatives that overcome the shortcomings of Pt(II) complexes. In this study, asplatin has been synthesized by fusing acetylsalicylic acid (aspirin) and cisplatin. Furthermore, it has been characterized using 1H NMR, mass spectrometry, elemental analysis, and UHPLC. A host-guest complex of asplatin and p-sulfocalix[4]arene (PSC4) has been developed and characterized using UV, Job's plot analysis, HPLC, and density functional theory (DFT) calculations. The experimental and computational investigations propose that a 1:1 complex between asplatin and PSC4 is formed. The stability constant of the designed complex has been determined using Job's plot and UHPLC and computed to be 9.1 × 104 M–1 and 8.7 × 104 M−1, which corresponds to a free energy of complexation of −6.8 kcal mol–1, while the calculated value for the inclusion free energy is −13.2 kcal mol−1. Both experimentally and theoretically estimated complexation free energy show that a stable host-guest complex can be formed in solution. The in vitro drug release study displayed the ability of the complex to release its cargo at a cancerous pH (pH of 5.5). Additionally, the asplatin/PSC4 complex is shown to be biocompatible when tested on human skin fibroblast noncancerous cells, demonstrating the highest in vitro cytotoxic activity against (MCF-7), cervical (HeLa), and lung cancer cells (A-549), with IC50 values of 0.75, 2.15, and 3.60 µg/mL, respectively. This is as compared to either cisplatin (IC50 of 5.47, 5.94 and 9.61 µg/mL, respectively) or asplatin (IC50 of 1.54, 5.05 and 3.91 µg/mL, respectively). On the other hand, the free asplatin exhibited higher cytotoxicity on cancerous cells and lower toxicity on noncancerous cells. The outcomes of the present joint theoretical and experimental investigation reinforce the interest in platinum-based anticancer therapeutics when they are protected from undesired interactions and suggest the use of the PSC4 macromolecule as a promising carrier for Pt(IV) anticancer drugs. The formed asplatin/PSC4 inclusion complex may represent an effective chemotherapeutic agent. [ABSTRACT FROM AUTHOR]

Because of its antioxidant, antimutagenic, and anti-infectious properties, epigallocatechin gallate (EGCG) is the most interesting compound among the green tea catechins polyphenols. However, its health effects are inconclusive due to its very low bioavailability, largely due to a particular instability that does not allow EGCG to reach the potency required for clinical developments. Over the last decade, many efforts have been made to improve the stability and bioavailability of EGCG using complex delivery systems such as nanotechnology, but these efforts have not been successful and easy to translate to industrial use. To meet the needs of a large-scale clinical trial requiring EGCG in a concentrated solution to anticipate swallowing impairments, we developed an EGCG-based aqueous solution in the simplest way while trying to circumvent EGCG instability. The solution was thoroughly characterized to sort out the unexpected stability outcome by combining experimental (HPLC-UV-mass spectrometry and infrared spectroscopy) and computational (density functional theory) studies. Against all odds, the EGCG–sucrose complex under certain conditions may have prevented EGCG from degradation in aqueous media. Indeed, in agreement with the ICH guidelines, the formulated solution was shown to be stable up to at least 24 months under 2–8 °C and at ambient temperature. Furthermore, considerable improvement in bioavailability in rats, against EGCG powder formulated in hard-gel capsules, was shown after gavage. Thus, the proposed formulation may provide an easily implementable platform to administer EGCG in the context of clinical development. [ABSTRACT FROM AUTHOR]

Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of depression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water solubility, and lessening the undesired effects of drugs. Because the atomic-level understanding of the β-CD–TCA inclusion complexes remains elusive, we carried out a comprehensive structural study via single-crystal X-ray diffraction and density functional theory (DFT) full-geometry optimization. Here, we focus on two complexes lining on the opposite side of the β-CD–TCA stability spectrum based on binding constants (Kas) in solution, β-CD–protriptyline (PRT) 1—most stable and β-CD–maprotiline (MPL) 2—least stable. X-ray crystallography unveiled that in the β-CD cavity, the PRT B-ring and MPL A-ring are aligned at a nearly perfect right angle against the O4 plane and primarily maintained in position by intermolecular C–H···π interactions. The increased rigidity of the tricyclic cores is arising from the PRT -CH=CH- bridge widens, and the MPL -CH2–CH2- flexure narrows the butterfly angles, facilitating the deepest and shallower insertions of PRT B-ring (1) and MPL A-ring (2) in the distorted round β-CD cavity for better complexation. This is indicated by the DFT-derived complex stabilization energies (ΔEstbs), although the complex stability orders based on Kas and ΔEstbs are different. The dispersion and the basis set superposition error (BSSE) corrections were considered to improve the DFT results. Plus, the distinctive 3D arrangements of 1 and 2 are discussed. This work provides the first crystallographic evidence of PRT and MPL stabilized in the β-CD cavity, suggesting the potential application of CDs for efficient drug delivery. [ABSTRACT FROM AUTHOR]

To improve physicochemical properties of vardenafil hydrochloride (VAR), its amorphous form and combinations with excipients—hydroxypropyl methylcellulose (HPMC) and β-cyclodextrin (β-CD)—were prepared. The impact of the modification on physicochemical properties was estimated by comparing amorphous mixtures of VAR to their crystalline form. The amorphous form of VAR was obtained as a result of the freeze-drying process. Confirmation of the identity of the amorphous dispersion of VAR was obtained through the use of comprehensive analysis techniques—X-ray powder diffraction (PXRD) and differential scanning calorimetry (DSC), supported by FT-IR (Fourier-transform infrared spectroscopy) coupled with density functional theory (DFT) calculations. The amorphous mixtures of VAR increased its apparent solubility compared to the crystalline form. Moreover, a nearly 1.3-fold increase of amorphous VAR permeability through membranes simulating gastrointestinal epithelium as a consequence of the changes of apparent solubility (Papp crystalline VAR = 6.83 × 10−6 cm/s vs. Papp amorphous VAR = 8.75 × 10−6 cm/s) was observed, especially for its combinations with β-CD in the ratio of 1:5—more than 1.5-fold increase (Papp amorphous VAR = 8.75 × 10−6 cm/s vs. Papp amorphous VAR:β-CD 1:5 = 13.43 × 10−6 cm/s). The stability of the amorphous VAR was confirmed for 7 months. The HPMC and β-CD are effective modifiers of its apparent solubility and permeation through membranes simulating gastrointestinal epithelium, suggesting a possibility of a stronger pharmacological effect. [ABSTRACT FROM AUTHOR]

Depression is a global threat. Tricyclic antidepressants (TCAs) are still efficacious in treating depression, albeit with more side effects. Cyclodextrins (CDs) with a suitable nanocavity are potential drug carriers and can enhance the drug bioavailability. Aiming for an atomistic understanding of the CD encapsulation facilitating the improvement of drug stability and the reduction of side effects, a comprehensive study series of the β-CD–TCA inclusion complexes through single crystal X-ray diffraction and density functional theory (DFT) calculation was undertaken. This work reports the supramolecular complexes of β-CD with two pivotal TCAs, clomipramine (CPM; 1) and doxepin (DXP; 2). The different inclusion topologies of the β-CD–TCA complexes were notable. X-ray analysis revealed that, in 1, the CPM B-ring (without chloro group) was entrapped in the β-CD cavity, whereas, in 2, the E-DXP A-ring and the Z-DXP B-ring were disordered in the cavity, yielding energetically favorable complexes primarily maintained by intermolecular C–H⋯π interactions, as indicated by DFT calculation. Because both wings of TCAs were similar, an alternative inclusion scenario of the A-ring was evidenced crystallographically in four other TCA complexes. The enhanced TCA thermodynamic stabilities via CD inclusion complexation helped to reduce the side effects and to increase the bioavailability. Moreover, the scrutinization of six TCAs in different lattice circumstances revealed the greater TCA structural flexibilities for their optimum pharmacological activity while binding with proteins. [ABSTRACT FROM AUTHOR]

Cycas pectinata Buch.-Ham. is commonly used in folk medicine against various disorders. The present study investigated the antidepressant and cytotoxicity activity of methanol extract of C. pectinata (MECP) along with quantitative phytochemical analysis by GC-MS method. Here, the GC-MS study of MECP presented 41 compounds, among which most were fatty acids, esters, terpenoids and oximes. The antidepressant activity was assessed by the forced swimming test (FST) and tail suspension test (TST) models. In contrast, MECP (200 and 400 mg/kg) exhibited a significant and dose-dependent manner reduction in immobility comparable with fluoxetine (10 mg/kg) and phenelzine (20 mg/kg). MECP showed a weak toxicity level in the brine shrimp lethality bioassay (ED50: 358.65 µg/mL) comparable to the standard drug vincristine sulfate (ED50: 2.39 µg/mL). Three compounds from the GC-MS study were subjected to density functional theory (DFT) calculations, where only cyclopentadecanone oxime showed positive and negative active binding sites. Cyclopentadecanone oxime also showed a good binding interaction in suppressing depression disorders by blocking monoamine oxidase and serotonin receptors with better pharmacokinetic and toxicological properties. Overall, the MECP exhibited a significant antidepressant activity with moderate toxicity, which required further advance studies to identify the mechanism. [ABSTRACT FROM AUTHOR]

This work details the study of the redox behavior of the drugs cyclobenzaprine (CBP), amitriptyline (AMP) and nortriptyline (NOR) through voltammetric methods and computational chemistry. Results obtained in this study show that the amine moiety of each compound is more likely to undergo oxidation at 1a at Ep1a ≈ 0.69, 0.79, 0.93 V (vs. Ag/AgCl/KClsat) for CBP, AMP and NOR, respectively. Moreover, CBP presented a second peak, 2a at Ep2a ≈ 0.98 V (vs. Ag/AgCl/KClsat) at pH 7.0. Furthermore, the electronic structure calculation results corroborate the electrochemical assays regarding the HOMO energies of the lowest energy conformers of each molecule. The mechanism for each anodic process is proposed according to electroanalytical and computational chemistry findings, which show evidence that the methods herein employed may be a valuable alternative to study the redox behavior of structurally similar drugs. [ABSTRACT FROM AUTHOR]