Halogen Substituents Research Articles

Comprehensive assessment of schiff base derived from 4-Chloroaniline and 2-Formylphenol: Molecular architecture, experimental with computational bioactivity profiling, emphasizing anticancer efficacy against pulmonary and mammary carcinoma cell models

This study thoroughly analyses the structural and biological properties of a Schiff base compound synthesized from the condensation of 2-formyl phenol and 4-chloroaniline. Single crystal X-ray diffraction examination indicated that the compound crystallizes in the monoclinic space group P21/c, with unit cell parameters a = 13.4232(15) Å, b = 5.7860(6) Å, c = 14.699(2) Å, β = 106.048(6) °, and Z = 4. The molecular structure has an E configuration around the C = N double bond, with a bond length of 1.266(2) Å, and includes an intramolecular O—H⋯N hydrogen bond. Hirshfeld surface analysis elucidated intermolecular interactions inside the crystal lattice, emphasizing dominant hydrogen-hydrogen, hydrogen-chlorine, and carbon-hydrogen contacts. The chemical exhibited concentration-dependent antioxidant and anti-inflammatory effects. Studies on DNA interactions indicate van der Waals forces between the ligand and nucleic acid, whereas it demonstrated considerable binding affinity for BSA with a ΔG value of -6.9 kcal/mol. ADME study revealed values within the recommended range, indicating advantageous pharmacokinetic characteristics. PASS filter-based cytotoxicity predictions indicated significant anti-cancer efficacy against breast adenocarcinoma, small cell lung carcinoma, and lung cancer. Toxicological assessments in diverse models indicated no possible irritation to skin and ocular tissues, highlighting its safety profile for therapeutic use. This research advances our comprehension of Schiff bases with halogen substituents and their prospective uses in chemistry and biology.

Preparation of cysteine-functionalized graphene quantum dots – Zinc phthalocyanines supramolecular hybrid system and their sono-photochemical studies

Current PDT agents often suffer from low singlet oxygen quantum yields, photobleaching, and poor biocompatibility. To address these issues, we propose novel PDT agents that combine the synthesized phthalocyanines with cysteine-functionalized graphene quantum dots (cys-GQDs) for the first time. This combination aims to enhance singlet oxygen production and improve solubility in biological media. In this way, new zinc phthalocyanines with halogen substituents were synthesized for potential use in photodynamic therapy (PDT). Specifically, 2-Bromo-4-methylphenol zinc (II) phthalocyanine (2a) and 2-chloro-4-methylphenol zinc(II) phthalocyanine (2b) and their graphene quantum dots derivatives were synthesized and characterized. The photochemical, sonochemical, and sono-photochemical properties of these compounds were analyzed, focusing on their efficiency in singlet oxygen production. Our studies of the 2a@cys-GQDs and 2b@cys-GQDs conjugates demonstrated higher singlet oxygen yields, suggesting their enhanced potential for clinical applications.

Efficient Derivatization of a Thienobenzobisthiazole-Based π-Conjugated Polymer Through Late-Stage Functionalization Towards High-Efficiency Organic Photovoltaic Cells.

Derivatization is essential for optimizing organic material properties. However, because functional groups are often introduced at an early stage of the synthesis, similar intermediates have to be repeatedly synthesized to produce derivatives, which amounts to a daunting and time-consuming task. Using thienobenzobisthiazole (TBTz) as a building unit of donor polymers for organic photovoltaics (OPVs), we demonstrate an efficient derivatization of a TBTz-based π-conjugated polymer by late-stage functionalization. In the developed synthetic route, functional groups are introduced at the last step of monomer synthesis, enabling us to easily synthesize several derivatives from a common intermediate. Ester and acyl groups are introduced into the polymer instead of the alkyl group, giving rise to deep HOMO energy levels and resulting in OPV cells with high open-circuit voltage even in the absence of halogen substituents that are typically introduced into the donor polymers. Notably, the ester-functionalized TBTz-based polymer shows a small nonradiative voltage loss (ΔVnr) of 0.19 V and has one of the highest charge generation efficiencies among the halogen-free donor polymers with similar ΔVnr, improving the critical trade-off relationship between voltage loss and charge generation. Our results provide an important guideline for the efficient development of high-performance polymers for OPVs.

Efficient Derivatization of a Thienobenzobisthiazole‐Based π‐Conjugated Polymer Through Late‐Stage Functionalization Towards High‐Efficiency Organic Photovoltaic Cells

AbstractDerivatization is essential for optimizing organic material properties. However, because functional groups are often introduced at an early stage of the synthesis, similar intermediates have to be repeatedly synthesized to produce derivatives, which amounts to a daunting and time‐consuming task. Using thienobenzobisthiazole (TBTz) as a building unit of donor polymers for organic photovoltaics (OPVs), we demonstrate an efficient derivatization of a TBTz‐based π‐conjugated polymer by late‐stage functionalization. In the developed synthetic route, functional groups are introduced at the last step of monomer synthesis, enabling us to easily synthesize several derivatives from a common intermediate. Ester and acyl groups are introduced into the polymer instead of the alkyl group, giving rise to deep HOMO energy levels and resulting in OPV cells with high open‐circuit voltage even in the absence of halogen substituents that are typically introduced into the donor polymers. Notably, the ester‐functionalized TBTz‐based polymer shows a small nonradiative voltage loss (ΔVnr) of 0.19 V and has one of the highest charge generation efficiencies among the halogen‐free donor polymers with similar ΔVnr, improving the critical trade‐off relationship between voltage loss and charge generation. Our results provide an important guideline for the efficient development of high‐performance polymers for OPVs.

Synthesis of kanamycin-azole hybrids and investigation of their antifungal activities

The World Health Organization (WHO) recognizes Candida albicans and Cryptococcus neoformans as the critical priority fungal pathogens for which therapeutic solutions are needed. Azole-based antifungal agents, including triazoles, diazoles, and thiazoles, are widely used in the treatments for fungal infections. In light of past successes in the transformation of antibacterial kanamycin into antifungal derivatives via chemical modifications, a new library of kanamycin-azole hybrids was synthesized and tested against a panel of azole-resistant and susceptible Candida and Cryptococcus strains. Structure activity relationship (SAR) studies revealed pivotal roles for antifungal activity of the azole ring (imidazole vs triazole) and halogen substituents on the benzene ring (F vs Cl). Most notably, hybrids 13, 14 and 15 were active against resistant C. albicans, C. tropicalis and C. neoformans strains and non-toxic towards mammalian cells. Mode of action investigations using fluorogenic dyes, (SYTOXTM) showed the fungal active compounds could permeabilize fungal membranes even at ¼ MICs. These findings reveal novel azole-based antifungals that could offer new therapeutic options for candidiasis and cryptococcosis.

Effect of Halogen Substituents on Charge Transport Properties of n-type Organic Semiconductors: A Theoretical Study.

Organic semiconductors (OSCs) have received significant attention as promising materials for electronic devices. In this study, we investigate the impact of halogen groups on the charge transport properties of n-type OSC-6,13 bis((triisopropylsilyl)ethynyl)-5,7,12,14-tetraazapentacene (TIPS-TAP). The computed mobilities for TIPS-TAPs substituted with F and Cl exhibit excellent agreement with the experimental values, while the simulation overestimates the electron mobility for TIPS-TAP. Interestingly, the mobility of TIPS-TAP-4F is significantly lower than that of TIPS-TAP-4Cl/Br, despite their similar packing structures. This discrepancy can be attributed to the strong electron-withdrawing effect of fluoride, which reduces the electron transfer integral and increases the reorganization energy. While molecular packing is widely recognized as a dominant factor in charge transport in OSCs, our study highlights the crucial role of electronic effects in charge transport in OSCs. This study provides new insights into the mechanisms underlying charge transport in OSCs.

Indole analogs as potential anti-breast cancer agents: Design, synthesis, in-vitro bioevaluation with DFT, molecular docking and ADMET studies

Being a belligerent malignancy, triple-negative breast cancer poses unmet clinical challenges due to lack of targeted therapy, rapid growth rate and metastasis, high heterogeneity, and increased risk of recurrence. Diverse 1-(1H-indol-1-yl)-2-((5-aryl-4H-1,2,4-triazol-3-yl)thio))ethanones have been synthesized in substantial yield (81-87 %) by clubbing 1-(chloroacetyl)indoles with substituted triazoles under refluxing conditions of 4-5 h. The indole integrates demonstrated substantial antitumor efficacy in the MTT assay against the MDA-MB-231 cell line and substituting indole moiety with a halogen (bromo) significantly improves the anti-breast cancer action of the synthesized hybrids compared to the unsubstituted ring. Compound 4i featuring halogen substituent on both the indole and phenyl moieties displayed the highest anticancer action with an IC50 value of 2.121 μM The synthetic variants exhibited a notable binding propensity against the EGFR-TK receptor (PDB ID:1M17). Through in-silico ADMET screening, the pharmacological proclivity of the title compounds has been convicted. The notable bioactivity of the indole hybrids projects them as a potential lead in developing anti-breast cancer medications, especially against TNBC.

Unveiling chlorine's role: How it shapes the formation and light-activated oxygen dynamics of chlorophenol-derived environmental persistent free radicals

Environmental persistent free radicals (EPFRs) derived from chlorophenols, triggered by light or heat exposure, pose significant ecological concerns, yet the impact of chlorine substituents on EPFRs formation and reactivity remains inadequately understood. Through an intentional synthesis of chlorophenol-derived EPFRs with varying chlorine contents and positioning, we elucidated the role of chlorine in the photoactivation of molecular oxygen. Our combined experimental and theoretical analysis reveals that these EPFRs are primarily oxygen-centered phenoxy radicals, establishing a direct link between chlorine substitution patterns and their ability to activate molecular oxygen under visible light. Increased chlorine content enhances EPFRs formation by elevating the positive charge on the phenolic hydroxyl group’s hydrogen atom, facilitating its removal. Moreover, the capability of EPFRs to activate molecular oxygen was directly correlated with chlorine content, with 2,3,5,6-tetrachlorophenol-derived EPFRs showcasing the highest activity. This activity is attributed to their structural propensity for TCSQ·- species generation. Furthermore, our study established a significant correlation between the toxicity and activity of EPFRs, emphasizing the critical role of halogen substituents in determining the reactivity of EPFRs. These insights contribute to our understanding of their environmental and toxicological ramifications, underscoring the imperative for continued research aimed at mitigating their detrimental impacts.

Synthesis and nootropic activity prediction of some 4-(aminomethyl)-1-benzylpyrrolidin-2-one derivatives structurally related with nebracetam

The aim. Search for new biologically active substances with improved nootropic parameters among analogues of 4-(aminomethyl)-1-benzylpyrrolidine-2-one (Nebracetam). Materials and methods. The required reagents were purified using standard techniques. The elemental analysis was performed on a "Hewlett Packard" automatic analyzer M-180 company. 1H NMR spectra were recorded on Varian Gemini 400 MHz spectrometer in DMSO-d6 as a solvent. LC/MS spectra were recorded with a PE SCIEX API 150EX liquid chromatograph equipped. The Autodock 4.2 software package was used for molecular docking. The active centers of the peptides (PDB ID: 5CXV, 6PV7) was used as the biologycal targets. Results and discussion. Basic and alternative methods (1 and 2) of obtaining were used to synthesise target analogues of 4-(aminomethyl)-1-R-benzylpyrrolidine-2-one. As a result of synthetic studies, an optimized method with an alternative method has been proposed. The advantages include reducing the duration and number of synthesis stages and avoiding the use of sodium azide, a highly toxic and hazardous substance. Molecular docking of the synthesized compounds at well-documented acetylcholine receptor sites indicates that all tested molecules will contribute to the manifestation of nootropic activity to varying degrees through cholinergic neurotransmission mechanisms. This is evidenced by the calculated docking values in relation to the muscarinic target. According to the docking results, it was found that depending on the enantiomeric configuration, the molecules formed stable complexes with the target and had characteristic binding modes both in the orthosteric site and in the extracellular vestibule (site of positive allosteric modulation of mAChR). It indicates the prospects of modifying the "nebracetam scaffold" at the phenyl fragment with halogen substituents. Conclusions. An effective method for synthesising analogues of 4-(aminomethyl)-1-R-benzylpyrrolidin-2-ones has been developed. The molecular docking revealed potential mechanisms of nootropic action of the synthesized derivatives as potential agonists and positive allosteric modulators of the muscarinic receptor

Synthesis and biological evaluation of novel aminoquinolines with an n-octyl linker: Impact of halogen substituents on C(7) or a terminal amino group on anticholinesterase and BACE1 activity

Alzheimer’s disease is age-related multifactorial neurodegenerative disease manifested by gradual loss of memory, cognitive decline and changes in personality. Due to rapid and continuous growth of its prevalence, the treatment of Alzheimer’s disease calls for development of new and efficacies drugs, especially those that could be able to simultaneously act on more than one of possible targets of action. Aminoquinolines have proven to be a highly promising structural scaffold in the design of such a drug as cholinesterases and β-secretase 1 inhibitors. In this study, we synthesised twenty-two new 4-aminoquinolines with different halogen atom and its position in the terminal N-benzyl group or with a trifluoromethyl or a chlorine as C(7)-substituents on the quinoline moiety. All compounds were evaluated as multi-target-directedligands by determining their inhibition potency towards human acetylcholinesterase, butyrylcholinesterase and β-secretase 1. All of the tested derivatives were very potent inhibitors of human acetylcholinesterase and butyrylcholinesterase with inhibition constants (Ki) in the nM to low μM range. Most were estimated to be able to cross the blood–brain barrier by passive transport and were nontoxic toward cells that represented the main models of individual organs.

A Structure-Activity Relationship Study on the Antioxidant Properties of Dithiocarbamic Flavanones.

The antioxidant properties of 3-dithiocarbamic flavanones have been investigated. The influence of the halogen substituents on ring A of the flavanones and the nature of the secondary amine from the dithiocarbamic moiety have been accounted. The results indicated that the presence of a halogen substituent at the C-8 position of the benzopyran ring induce better antioxidant properties against DPPH and ABTS than butylated hydroxytoluene (BHT) and ascorbic acid. The presence of a halogen substituent at the mentioned position appears to induce a higher stability for a free radical intermediate at the C-3 position of the benzopyran ring. A free radical enolate is most likely to be involved in the antioxidant activity of this dithiocarbamic flavanone. It is a stable intermediate that supports the influence of dithiocarbamic moiety on the antioxidant properties of the reported flavanones.

Design and characterization of novel broadband chalcone-based THz optical crystals

By combining extended π-conjugated structures and halogen substituents, two novel chalcone-based optical THz crystals were designed: CBC (C22H17ClO2, Pc) and TFBC (C23H17F3O2, P21). These crystals were synthesized and successfully grown using the solution evaporation method. The effects of different types and quantities of halogen substituents on hydrogen bonding interactions, molecular alignment, and nonlinear strength were analyzed. The second harmonic generation (SHG) efficiency, thermal stability, transmission spectra, dielectric constant, and THz generation of the crystals were characterized. Theoretical calculations were conducted to determine the hyperpolarizability, band gap, density of states, and nonlinear optical coefficients of the crystals. The results showed that the synthesized crystals exhibited higher transparency (≥85%) and SHG efficiencies of 9.5 times and 6.2 times that of standard potassium dihydrogen phosphate (KDP), respectively, compared to previously reported chalcone NLO crystals. For the first time, the THz generation efficiency of the two crystals was confirmed through the optical rectification method, with TFBC demonstrating a wider THz spectrum range compared to CBC.

Utilizing Secondary Bonds Formed by Halogen Substituents: Achieving the Dynamic Transition of Low-Bandgap Semiconductor Polymers from Macromolecules to Small Molecules

Utilizing Secondary Bonds Formed by Halogen Substituents: Achieving the Dynamic Transition of Low-Bandgap Semiconductor Polymers from Macromolecules to Small Molecules

All‐Small‐Molecule Ternary Organic Solar Cell with 16.35% Efficiency Enabled by Chlorinated Terminal Units

In the last few years, there have been notable developments in organic solar cells using both small molecule donor and acceptor. It has been noted that adding halogens to the end groups of small molecules could enhance the film structure and, consequently, the performance of the devices. In this study, three novel small molecule donors are created. The molecules include a vinyl‐CPDT oligomer with three units, with end‐caps made up of indanedione groups and containing four H, four Cl, and four F substituents. The purpose of the study is to investigate how the halogen substituent affects the photovoltaic characteristics of binary devices made with the non‐fullerene acceptor (NFA) TOCR2 as the acceptor. Having the halogen in the device enhances its effectiveness, and FG5, which has 4‐Cl substituents in the end groups, shows the highest efficiency among all devices with a PCE of 14.39%. Incredibly, the ternary device that is created in normal atmospheric conditions with chloro‐substituted FG5 as the donor, TOCR2 as the acceptor, and the wide band gap NFA DICTF as the third element shows significantly improved efficiency, achieving PCE values of up to 16.35%.

Photochemical degradation of bisphenol S and its tetrahalogenated derivatives in water

Bisphenol S (BPS), a widely used plasticizer, is known to have potential endocrine disrupting effects to organisms. Its tetrahalogenated derivatives, tetrachlorobisphenol S (TCBPS) and tetrabromobisphenol S (TBBPS), are flame retardants exhibiting high neurodevelopmental toxicity and cytotoxicity. Halogen substitution has been shown to significantly affect the optical and photochemical properties of organic compounds. In this study, we conducted a comparative investigation into the photochemical behaviors of BPS, TCBPS, and TBBPS in aqueous solutions under both laboratory UV and natural sunlight irradiation. Spectroscopic titration results indicated that the pKa of TCBPS (4.16) and TBBPS (4.13) are approximately 3.7 units smaller than that of BPS (7.85), indicating that the halogenated derivatives are mainly present as the phenolate anions under circumneutral conditions. The halogen substituents also cause a significant bathochromic shift in the absorption spectra of TCBPS and TBBPS compared to BPS, leading to the enhanced absorption of sunlight. Meanwhile, TCBPS and TBBPS showed higher quantum yields than BPS, attributed to the "heavy atom" effect of halogen substituents. GCSOLAR modeling predicted half-lives for BPS, TCBPS, and TBBPS in surface water in Nanjing (32°2′7.3′′N, 118°50′21′′E) under noon sunlight in clear mid-autumn days as 810.2, 3.4, and 0.7 min, respectively. Toxicity evaluation suggest potential ecological risks of BPS/TCBPS/TBBPS and their photoproducts to aquatic organisms. Our findings highlight direct photolysis as an important mechanism accounting for the attenuation of tetrahalogenated bisphenols in both sunlit surface waters and UV based water treatment processes.engineered (e.g., UV disinfection) and natural aquatic environments (e.g., surface fresh waters).

Influence of halogen substituents on sensitivity towards detonation of polycyclic nitroaromatic high‐energy molecules

AbstractAnalysis of molecular electrostatic potential (MEP) on the surface of high‐energy molecules is often used to predict detonation properties of these compounds since strong positive values of electrostatic potentials in the central molecular regions are related to the high sensitivity towards detonation. In this work, we combined bond dissociation energy (BDE) calculations with analysis of the MEPs to reveal the influence of the halogen substituents on the sensitivities towards detonation of a series of halogen‐substituted dinitronaphthalenes. Obtained results showed that halogen substituents affect detonation properties of the studied molecules by tilting the neighboring NO2 groups, which results in decreased stability of corresponding C–N bonds. In addition, halogen atoms affect the detonation properties of studied molecules by modifying the positive values of the electrostatic potentials in the central regions of the molecular surfaces.

Tuning phenolic hemicyanines for ratiometric DNA sensing and live cell nuclear bioimaging applications

Activatable fluorescent probes with turn-on emission in response to a biological target can reduce the background signal and improve the detection limit needed for biosensor and bioimaging resolution. Turn-on probes with dual emission (ratiometric probes) have further advantages, as they have self-calibration ability for more reliable detection. Herein, we demonstrate the tunability of the phenolic hemicyanine (HC) scaffold for both DNA biosensing and bioimaging applications using the quinine-binding DNA aptamer (MN4) as a host-guest biosensor platform and live ovarian cancer cells for nuclear imaging. The DNA aptamer MN4 contains a three-way junction (3WJ) consisting of a hydrophobic branch point connecting three double-stranded stems. Phenolic HCs bearing electron-withdrawing halogen substituents (FPhOBtz and Cl2PhOBTz) bind to the 3WJ of MN4 as the phenolate with strong turn-on emission. Subsequent displacement of the phenolate by the quinine target causes a turn-off emission response. In contrast, the parent phenolic HC (PhOBtz) and those bearing electron-donating groups (Me2PhOBtz and (MeO)2PhOBtz) exhibit dual (phenol and phenolate) fluorescence upon MN4 binding. Phenol excitation generates phenolate emission by an excited-state proton transfer (ESPT) process with DNA components serving as the proton acceptor. Quinine displacement of PhOBtz from the 3WJ of MN4 affords a turn-on ratiometric response with preferential light-up of phenol emission. The ability of the phenolic HCs to serve as cellular nuclear stains further highlights the tunability of the phenolic HC probes with the Cl2PhOBtz analog displaying superior staining ability. The simplicity and tunability of phenolic HCs make them attractive fluorescent probes for DNA sensing and bioimaging applications.

Synthesis, biological evaluation, and molecular modelling of substituted thiazolyl thiourea derivatives: A new class of prolyl oligopeptidase inhibitors

Prolyl oligopeptidase (POP) is a compelling therapeutic target associated with aging and neurodegenerative disorders due to its pivotal role in neuropeptide processing. Despite initial promise demonstrated by early-stage POP inhibitors, their progress in clinical trials has been halted at Phase I or II. This impediment has prompted the pursuit of novel inhibitors. The current study seeks to contribute to the identification of efficacious POP inhibitors through the design, synthesis, and comprehensive evaluation (both in vitro and in silico) of thiazolyl thiourea derivatives (5a-r). In vitro experimentation exhibited that the compounds displayed significant higher potency as POP inhibitors. Compound 5e demonstrated an IC50 value of 16.47 ± 0.54 μM, representing a remarkable potency. A meticulous examination of the structure-activity relationship indicated that halogen and methoxy substituents were the most efficacious. In silico investigations delved into induced fit docking, pharmacokinetics, and molecular dynamics simulations to elucidate the intricate interactions, orientation, and conformational changes of these compounds within the active site of the enzyme. Moreover, our pharmacokinetic assessments confirmed that the majority of the synthesized compounds possess attributes conducive to potential drug development.

Propanediamine modified pillar[5]arene: A novel stationary phase for the high selectivity separation of versatile analytes

The unique properties of pillar[5]arene, including hydrophobic cavities, π-π conjugated and easy modification, make it a promising candidate as stationary phase for HPLC. Herein, we fabricated a novel propanediamine modified pillar[5]arene bonded silica as the stationary phase (PDA-BP5S) for reversed-phase liquid chromatography (RPLC). Benefiting from the significant hydrophobicity, π-π conjugative, p-π effect, and hydrogen bonding, the PDA-BP5S packed column showed high separation performance of versatile analytes involving polycyclic aromatic hydrocarbons, alkyl benzenes, phenols, arylamine, phenylethane/styrene/ phenylacetylene, toluene/m-xylene/mesitylene, halobenzenes, benzenediol and nitrophenol isomers. Especially, the separation of halobenzenes appeared to be controlled by both the size of the halogen substituents and the strength of the noncovalent bonding interactions, which was further confirmed by molecular dynamics simulation. The satisfactory separation and repeatability revealed the promising prospects of amine-pillar[5]arene-based stationary phase for RPLC.

Investigation of the temperature dependence of the dielectric relaxation of chlorobenzene, bromobenzene and iodobenzene

This paper deals with the investigation results of temperature dependence of complex permittivity’sε∗ = έ − iε˝ of chloro, bromo and iodo- benzene at wavelength 11,50 cm and 12,80 cm within the temperature range 20 ÷ -80˚. It is established that dielectric properties of given liquids are characteristic of one relaxation time. The dielectric spectra were studied taking into account other frequencies given in the literature. In all investigated liquids, a jump appears in the real and imaginary parts of the complex permittivity at the point of the phase transition. The temperature dependence of the dielectric relaxation time of molecules in the liquid state has been determined. It was found that with an increase in the amount of the halogen substituent, an increase in the relaxation time occurs. Macroscopic and molecular relaxation times were calculated from the experimental values. The thermodynamic quantities characterizing the process of dielectric relaxation are calculated. The activation enthalpy of dielectric relaxation processes is compared. The studies were carried out using the dielectric spectroscopy method. This method allows a more detailed study of the dielectric properties of the objects of study due to the large equilibrium (“static”) dielectric constant of the object. It has been determined that the height of the potential barrier separating the two equilibrium positions of a polar molecule is greatest in the state of a pure polar liquid and decreases with dilution in a non-polar solvent.