Synthesis, In Vivo Anticonvulsant Activity Evaluation and In Silico Studies of Some Quinazolin-4(3H)-One Derivatives.

Two series, "a" and "b", each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABAA receptor at the benzodiazepine binding site and inhibitors of carbonic anhydrase II. Quinazolin-4(3H)-one derivatives were evaluated in vivo (D1-3 = 50, 100, 150 mg/kg, administered intraperitoneally) using the pentylenetetrazole (PTZ)-induced seizure model in mice, with phenobarbital and diazepam, as reference anticonvulsant agents. The in silico studies suggested the compounds act as anticonvulsants by binding on the allosteric site of GABAA receptor and not by inhibiting the carbonic anhydrase II, because the ligands-carbonic anhydrase II predicted complexes were unstable in the molecular dynamics simulations. The mechanism targeting GABAA receptor was confirmed through the in vivo flumazenil antagonism assay. The pentylenetetrazole experimental anticonvulsant model indicated that the tested compounds, 1a-9a and 1b-9b, present a potential anticonvulsant activity. The evaluation, considering the percentage of protection against PTZ, latency until the onset of the first seizure, and reduction in the number of seizures, revealed more favorable results for the "b" series, particularly for compound 8b.

Discovery of A Novel Series of Quinazoline-Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents.

Considering the pivotal role of angiogenesis in solid tumor progression, we developed a novel series of quinazoline-thiazole hybrids (SA01-SA07) as antiproliferative and anti-angiogenic agents. Four out of the seven compounds displayed superior antiproliferative activity (IC50 =1.83-4.24 µM) on HepG2 cells compared to sorafenib (IC50 = 6.28 µM). The affinity towards the VEGFR2 kinase domain was assessed through in silico prediction by molecular docking, molecular dynamics studies, and MM-PBSA. The series displayed a high degree of similarity to sorafenib regarding the binding pose within the active site of VEGFR2, with a different orientation of the 4-substituted-thiazole moieties in the allosteric pocket. Molecular dynamics and MM-PBSA evaluations identified SA05 as the hybrid forming the most stable complex with VEGFR2 compared to sorafenib. The impact of the compounds on vascular cell proliferation was assessed on EA.hy926 cells. Six compounds (SA01-SA05, SA07) displayed superior anti-proliferative activity (IC50 = 0.79-5.85 µM) compared to sorafenib (IC50 = 6.62 µM). The toxicity was evaluated on BJ cells. Further studies of the anti-angiogenic effect of the most promising compounds, SA04 and SA05, through the assessment of impact on EA.hy296 motility using a wound healing assay and in ovo potential in a CAM assay compared to sorafenib, led to the confirmation of the anti-angiogenic potential.

Novel Flurbiprofen Derivatives as Antioxidant and Anti-Inflammatory Agents: Synthesis, In Silico, and In Vitro Biological Evaluation.

In this study, we present the synthesis of five novel compounds by combining flurbiprofen with various substituted 2-phenethylamines. The synthesized derivatives underwent comprehensive characterization using techniques such as 1H- and 13C-NMR spectroscopy, UV-Vis spectroscopy, and high-resolution mass spectrometry (HRMS). Detailed HRMS analysis was performed for each of these newly created molecules. The biological activities of these compounds were assessed through in vitro experiments to evaluate their potential as anti-inflammatory and antioxidant agents. Furthermore, the lipophilicity of these derivatives was determined, both theoretically using the cLogP method and experimentally through partition coefficient (RM) measurements. To gain insights into their binding affinity, we conducted an in silico analysis of the compounds' interactions with human serum albumin (HSA) using molecular docking studies. Our findings reveal that all of the newly synthesized compounds exhibit significant anti-inflammatory and antioxidant activities, with results statistically comparable to the reference compounds. Molecular docking studies further explain the observed in vitro results, shedding light on the molecular mechanisms behind their biological activities. Using in silico method, toxicity was calculated, resulting in LD50 values. Depending on the administration route, the novel flurbiprofen derivatives show lower toxicity compared to the standard flurbiprofen.

An Overview of the Structure-Activity Relationship in Novel Antimicrobial Thiazoles Clubbed with Various Heterocycles (2017-2023).

Antimicrobial resistance is an increasing problem for global public health. One of the strategies to combat this issue is the synthesis of novel antimicrobials through rational drug design based on extensive structure-activity relationship studies. The thiazole nucleus is a prominent feature in the structure of many authorized antimicrobials, being clubbed with different heterocycles. The purpose of this review is to study the structure-activity relationship in antimicrobial thiazoles clubbed with various heterocycles, as reported in the literature between 2017 and 2023, in order to offer an overview of the last years in terms of antimicrobial research and provide a helpful instrument for future research in the field.

Discovery of New Hydrazone-Thiazole Polyphenolic Antioxidants through Computer-Aided Design and In Vitro Experimental Validation.

Oxidative stress is linked to a series of diseases; therefore, the development of efficient antioxidants might be beneficial in preventing or ameliorating these conditions. Based on the structure of a previously reported compound with good antioxidant properties and on computational studies, we designed several catechol derivatives with enhanced antioxidant potential. The compounds were synthesized and physicochemically characterized, and their antioxidant activity was assessed through different antiradical, electron transfer and metal ions chelation assays, their electrochemical behavior and cytotoxicity were studied. The results obtained in the in vitro experiments correlated very well with the in silico studies; all final compounds presented very good antioxidant properties, generally superior to those of the reference compounds used. Similarly, the results obtained from studying the compounds' electrochemical behavior were in good agreement with the results of the antioxidant activity evaluation assays. Regarding the compounds' cytotoxicity, compound 7b had a dose-dependent inhibitory effect against all cell lines. In conclusion, through computer-aided design, we developed several catechol thiazolyl-hydrazones with excellent antioxidant properties, of which compound 7b, with two catechol moieties in its structure, exhibited the best antioxidant activity.

HPLC Analysis and In Vitro and In Silico Evaluation of the Biological Activity of Polyphenolic Components Separated with Solvents of Various Polarities from Helichrysum italicum.

Helichrysum italicum has piqued the interest of many researchers in recent years, mostly for its essential oil, but increasingly for its polyphenolic content as well. In the current study, we examine the polyphenolic composition of H. italicum grown in Bulgaria. The polyphenolic complex was fractionated with solvents of various polarities, including hexane, chloroform, ethyl acetate, and butanol, in order to assess the biological impact of the components. HPLC-PDA and UHPLC-MS/MS were used to examine all fractions. The green coffee fingerprint profile was employed as a "surrogate standard" in the polyphenolic components detection approach. From the UHPLC-MS/MS analysis, we identified 60 components of the polyphenolic complex such as quercetin 3-O-glucuronide, quercetin acetyl-glycoside, isorhamnetin acetyl-glycoside, isorhamnetin caffeoyl-glycoside, quercetin caffeoyl-malonyl-glycoside, isorhamnetin coumaroyl-glycoside, coumaroyl-caffeoylquinic acid, and diCQA-acetyl-derivative were first reported in the composition of H. italicum. The biological activity of the fractions was evaluated in vitro and in silico, which included the fight against oxidative stress (hydrogen peroxide scavenging activity (HPSA), hydroxyl radical scavenging activity (HRSA), metal-chelating activity (MChA)) and nitrosative (nitric oxide scavenging activity) (NOSA)), in vitro anti-inflammatory, and anti-arthritic activity. Results are presented as IC50 ± SD µg/mL. The analysis showed that the EtOAc fraction was characterized by highest HPSA (57.12 ± 1.14 µg/mL), HRSA (92.23 ± 1.10 µg/mL), MChA (5.60 ± 0.17 µg/mL), and NOSA (89.81 ± 2.09 µg/mL), while the hexane and chloroform fractions showed significantly higher in vitro anti-inflammatory activity (30.48 ± 2.33 µg/mL, 62.50 ± 1.69 µg/mL) compared to the standard ibuprofen. All three fractions showed potential anti-arthritic activity (102.93 ± 8.62 µg/mL, 108.92 ± 4.42 µg/mL, 84.19 ± 3.89 µg/mL).

Agastache Species: A Comprehensive Review on Phytochemical Composition and Therapeutic Properties.

The Agastache genus is part of the Lamiaceae family and is native to North America, while one species, Agastache rugosa (A. rugosa), is native to East Asia. A review on the phytochemistry and bioactivity of Agastache genus was last performed in 2014. Since then, a lot of progress has been made on the characterization of the phytochemical and pharmacological profiles of Agastache species. Thus, the purpose of this paper is to present a summary of the findings on the phytochemistry and biological effects of several Agastache species, including both extracts and essential oil characterization. We performed a comprehensive search using PubMed and Scopus databases, following PRISMA criteria regarding the study selection process. The available data is focused mainly on the description of the chemical composition and bioactivity of A. rugosa, with fewer reports referring to Agastache mexicana (A. mexicana) and Agastache foeniculum (A. foeniculum). Agastache species are characterized by the dominance of flavonoids and phenolic acids, as well as volatile compounds, particularly phenylpropanoids and monoterpenes. Moreover, a series of pharmacological effects, including antioxidant, cytotoxic, antimicrobial, anti-atherosclerotic, and cardioprotective properties, have been reported for species from the Agastache genus.

Inclusion of a Catechol-Derived Hydrazinyl-Thiazole (CHT) in ß-Cyclodextrin Nanocavity and Its Effect on Antioxidant Activity: A Calorimetric, Spectroscopic and Molecular Docking Approach.

The aim of the present research was to obtain a supramolecular complex between a strong antioxidant compound previously reported by our group, in order to extend its antioxidant activity. The formation of the inclusion complex of a catechol hydrazinyl-thiazole derivative (CHT) and ß-cyclodextrin in aqueous solution has been investigated using isothermal titration calorimetry (ITC), spectroscopic and theoretical methods. The stoichiometry of this inclusion complex was established to be equimolar (1:1) and its equilibrium constant was determined. An estimation of the thermodynamic parameters of the inclusion complex showed that it is an enthalpy and entropy-driven process. Our observations also show that hydrophobic interactions are the key interactions that prevail in the complex. 1H NMR spectroscopic method was employed to study the inclusion process in an aqueous solution. Job plots derived from the 1H NMR spectral data demonstrated 1:1 stoichiometry of the inclusion complex in a liquid state. A 2D NMR spectrum suggests the orientation of the aromatic ring of CHT inside the ß-CD cavity. The antiradical activity of the complex was evaluated and compared with free CHT, indicating a delayed activity compared with free CHT. To obtain additional qualitative and visual insight into the particularity of CHT and ß-CD interaction, molecular docking calculations have been performed.

Structure-Activity Relationship Studies Based on Quinazoline Derivatives as EGFR Kinase Inhibitors (2017-Present).

The epidermal growth factor receptor (EGFR) plays a critical role in the tumorigenesis of various forms of cancer. Targeting the mutant forms of EGFR has been identified as an attractive therapeutic approach and led to the approval of three generations of inhibitors. The quinazoline core has emerged as a favorable scaffold for the development of novel EGFR inhibitors due to increased affinity for the active site of EGFR kinase. Currently, there are five first-generation (gefitinib, erlotinib, lapatinib, vandetanib, and icotinib) and two second-generation (afatinib and dacomitinib) quinazoline-based EGFR inhibitors approved for the treatment of various types of cancers. The aim of this review is to outline the structural modulations favorable for the inhibitory activity toward both common mutant (del19 and L858R) and resistance-conferring mutant (T790M and C797S) EGFR forms, and provide an overview of the newly synthesized quinazoline derivatives as potentially competitive, covalent or allosteric inhibitors of EGFR.

New Approaches on the Anti-Inflammatory and Cardioprotective Properties of Taraxacum officinale Tincture.

The present research investigated the in vivo anti-inflammatory and cardioprotective activities, as well as the antioxidant potential of Taraxacum officinale tincture (TOT), in relation to the polyphenolic composition. Chromatographic and spectrophotometric techniques were used to determine the polyphenolic profile of TOT and the antioxidant activity was preliminarily assessed in vitro by DPPH• and FRAP spectrophotometric methods. The in vivo anti-inflammatory and cardioprotective activities were studied in rat turpentine-induced inflammation and in rat isoprenaline-induced myocardial infarction (MI) models. The main polyphenolic compound identified in TOT was cichoric acid. The oxidative stress determinations showed the capacity of the dandelion tincture not only to decrease the total oxidative stress (TOS), the oxidative stress index (OSI), and the total antioxidant capacity (TAC), but also the malondialdehide (MDA), thiols (SH), and nitrites/nitrates (NOx) levels both in inflammation and MI models. In addition, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatin kinase-MB (CK-MB), and nuclear factor kappa B (NF-κB) parameters were decreased by the administration of the tincture. The results show that T. officinale could be considered a valuable source of natural compounds with important benefits in pathologies linked to oxidative stress.

Antioxidant Activity Evaluation and Assessment of the Binding Affinity to HSA of a New Catechol Hydrazinyl-Thiazole Derivative.

Polyphenols have attained pronounced attention due to their ability to provide numerous health benefits and prevent several chronic diseases. In this study, we designed, synthesized and analyzed a water-soluble molecule presenting a good antioxidant activity, namely catechol hydrazinyl-thiazole (CHT). This molecule contains 3',4'-dihydroxyphenyl and 2-hydrazinyl-4-methyl-thiazole moieties linked through a hydrazone group with very good antioxidant activity in the in vitro evaluations performed. A preliminary validation of the CHT developing hypothesis was performed evaluating in silico the bond dissociation enthalpy (BDE) of the phenol O-H bonds, compared to our previous findings in the compounds previously reported by our group. In this paper, we report the binding mechanism of CHT to human serum albumin (HSA) using biophysical methods in combination with computational studies. ITC experiments reveal that the dominant forces in the binding mechanism are involved in the hydrogen bond or van der Waals interactions and that the binding was an enthalpy-driven process. NMR relaxation measurements were applied to study the CHT-protein interaction by changing the drug concentration in the solution. A molecular docking study added an additional insight to the experimental ITC and NMR analysis regarding the binding conformation of CHT to HSA.

Safety of Antibiotics in Hospitalized Children in Romania: A Prospective Observational Study.

Antibiotics are among the most prescribed drugs in pediatric inpatients and are frequently associated with adverse drug reactions (ADRs) in children. This study aimed to assess the frequency and type of ADRs related to the use of antibiotics in pediatric inpatients through a prospective observational study, conducted over 6 months, covering the winter and spring seasons when the incidence of infections peaks in Romania. ADRs were evaluated for causality, avoidability and severity. Among the 266 included children, 25 (9.4%) experienced 30 ADRs. ADR frequency tended to be higher in ≤2-year-olds (13 of 25, 52.0%) than in other age categories. Gastrointestinal and hematological ADRs were most frequently observed. Diarrhea was the most common ADR associated with antibiotics (8 of 30, 26.7%). Ceftriaxone (16 of 30, 53.3%), cefuroxime, ceftazidime and azithromycin (3 of 30, 10.0% each) were most commonly responsible for ADRs. After causality assessment, 2 (6.7%) ADRs were considered definite, 12 (40.0%) probable and 16 (53.3%) possible. One ADR was classified as definitely avoidable and one as possibly avoidable. Seven children required treatment for ADRs. Antibiotic treatment was discontinued in 4 children. Antibiotics frequently caused ADRs in ≤ 2-year-olds and were commonly associated with gastrointestinal symptoms. Close monitoring of antibiotic-associated ADRs remains important in the pediatric population.

Synthesis of New Phenolic Derivatives of Quinazolin-4(3H)-One as Potential Antioxidant Agents-In Vitro Evaluation and Quantum Studies.

Considering the important damage caused by the reactive oxygen (ROS) and nitrogen (RNS) species in the human organism, the need for new therapeutic agents, with superior efficacy to the known natural and synthetic antioxidants, is crucial. Quinazolin-4-ones are known for their wide range of biological activities, and phenolic compounds display an important antioxidant effect. Linking the two active pharmacophores may lead to an increase of the antioxidant activity. Therefore, we synthesized four series of new hybrid molecules bearing the quinazolin-4-one and phenol scaffolds. Their antioxidant potential was evaluated in vitro, considering different possible mechanisms of action: hydrogen atom transfer, ability to donate electrons and metal ions chelation. Theoretical quantum and thermodynamical calculations were also performed. Some compounds, especially the ortho diphenolic ones, exerted a stronger antioxidant effect than ascorbic acid and Trolox.

Antioxidant and Cytotoxic Activity of New Polyphenolic Derivatives of Quinazolin-4(3H)-one: Synthesis and In Vitro Activities Evaluation.

The development of hybrid molecules with significant human therapeutic properties is one of the main approaches of pharmaceutical research. One of the most important pharmacophores is the quinazolin-4(3H)-one heterocycle moiety, due to its wide range of biological activities. By its derivatization with polyphenolic compounds, in our previous research, it proved to possess a good antiradical activity of ortho-diphenolic derivatives of quinazolin-4(3H)-one. In this study, we developed two new series of compounds, with an additional phenolic group or with a methyl group on the thioacetohydrazone fragment. The methods used to evaluate the activity of the compounds were radical scavenging, reduction of oxidizing reagents and transition metals' ions chelation assays. Quantum descriptors were also calculated in order to evaluate the influence of substituents and their position on the activity of the compounds. The cytotoxic activity was evaluated using normal human foreskin fibroblast cells (BJ) and two cancerous cell lines, lung adenocarcinoma cells (A549) and prostate carcinoma cells (LNCaP). The results obtained for the pyrogallol derivatives showed a high antioxidant activity compared to ascorbic acid and Trolox. All the synthesized compounds displayed a higher cytotoxicity against the cancerous cell types and a high cytocompatibility with the normal cells. The antioxidant activity was deeply influenced by the addition of the third phenolic group in the synthesized molecules.

Phenolic Thiazoles with Antioxidant and Antiradical Activity. Synthesis, In Vitro Evaluation, Toxicity, Electrochemical Behavior, Quantum Studies and Antimicrobial Screening.

Oxidative stress represents the underlying cause of many chronic diseases in human; therefore, the development of potent antioxidant compounds for preventing or treating such conditions is useful. Starting from the good antioxidant and antiradical properties identified for the previously reported Dihydroxy-Phenyl-Thiazol-Hydrazinium chloride (DPTH), we synthesized a congeneric series of phenolic thiazoles. The radical scavenging activity, and the antioxidant and chelation potential were assessed in vitro, a series of quantum descriptors were calculated, and the electrochemical behavior of the synthesized compounds was studied to evaluate the impact on the antioxidant and antiradical activities. In addition, their antibacterial and antifungal properties were evaluated against seven aerobic bacterial strains and a strain of C. albicans, and their cytotoxicity was assessed in vitro. Compounds 5a-b, 7a-b and 8a-b presented remarkable antioxidant and antiradical properties, and compounds 5a-b, 7a and 8a displayed good Cu+2 chelating activity. Compounds 7a and 8a were very active against P. aeruginosa ATCC 27853 compared to norfloxacin, and proved less cytotoxic than ascorbic acid against the human keratinocyte cell line (HaCaT cells, CLS-300493). Several phenolic compounds from the synthesized series presented excellent antioxidant activity and notable anti-Pseudomonas potential.

An Overview of the Synthesis and Antimicrobial, Antiprotozoal, and Antitumor Activity of Thiazole and Bisthiazole Derivatives.

Thiazole, a five-membered heteroaromatic ring, is an important scaffold of a large number of synthetic compounds. Its diverse pharmacological activity is reflected in many clinically approved thiazole-containing molecules, with an extensive range of biological activities, such as antibacterial, antifungal, antiviral, antihelmintic, antitumor, and anti-inflammatory effects. Due to its significance in the field of medicinal chemistry, numerous biologically active thiazole and bisthiazole derivatives have been reported in the scientific literature. The current review provides an overview of different methods for the synthesis of thiazole and bisthiazole derivatives and describes various compounds bearing a thiazole and bisthiazole moiety possessing antibacterial, antifungal, antiprotozoal, and antitumor activity, encouraging further research on the discovery of thiazole-containing drugs.

Novel 2,4-Disubstituted-1,3-Thiazole Derivatives: Synthesis, Anti-Candida Activity Evaluation and Interaction with Bovine Serum Albumine.

Herein we report the synthesis of two novel series of 1,3-thiazole derivatives having a lipophilic C4-substituent on account of the increasing need for novel and versatile antifungal drugs for the treatment of resistant Candida sp.-based infections. Following their structural characterization, the anti-Candida activity was evaluated in vitro while using the broth microdilution method. Three compounds exhibited lower Minimum Inhibitory Concentration (MIC) values when compared to fluconazole, being used as the reference antifungal drug. An in silico molecular docking study was subsequently carried out in order to gain more insight into the antifungal mechanism of action, while using lanosterol-C14α-demethylase as the target enzyme. Fluorescence microscopy was employed to further investigate the cellular target of the most promising molecule, with the obtained results confirming its damaging effect towards the fungal cell membrane integrity. Finally, the distribution and the pharmacological potential in vivo of the novel thiazole derivatives was investigated through the study of their binding interaction with bovine serum albumin, while using fluorescence spectroscopy.

Design, Synthesis and Biological Evaluation of New Piperazin-4-yl-(acetyl-thiazolidine-2,4-dione) Norfloxacin Analogues as Antimicrobial Agents.

 In an effort to improve the antimicrobial activity of norfloxacin, a series of hybrid norfloxacin-thiazolidinedione molecules were synthesized and screened for their direct antimicrobial activity and their anti-biofilm properties. The new hybrids were intended to have a new binding mode to DNA gyrase, that will allow for a more potent antibacterial effect, and for activity against current quinolone-resistant bacterial strains. Moreover, the thiazolidinedione moiety aimed to include additional anti-pathogenicity by preventing biofilm formation. The resulting compounds showed promising direct activity against Gram-negative strains, and anti-biofilm activity against Gram-positive strains. Docking studies and ADMET were also used in order to explain the biological properties and revealed some potential advantages over the parent molecule norfloxacin.

Design and Synthesis of Novel 1,3-Thiazole and 2-Hydrazinyl-1,3-Thiazole Derivatives as Anti-Candida Agents: In Vitro Antifungal Screening, Molecular Docking Study, and Spectroscopic Investigation of their Binding Interaction with Bovine Serum Albumin.

In the context of there being a limited number of clinically approved drugs for the treatment of Candida sp.-based infections, along with the rapid development of resistance to the existing antifungals, two novel series of 4-phenyl-1,3-thiazole and 2-hydrazinyl-4-phenyl-1,3-thiazole derivatives were synthesized and tested in vitro for their anti-Candida potential. Two compounds (7a and 7e) showed promising inhibitory activity against the pathogenic C. albicans strain, exhibiting substantially lower MIC values (7.81 µg/mL and 3.9 µg/mL, respectively) as compared with the reference drug fluconazole (15.62 µg/mL). Their anti-Candida activity is also supported by molecular docking studies, using the fungal lanosterol C14α-demethylase as the target enzyme. The interaction of the most biologically active synthesized compound 7e with bovine serum albumin was investigated through fluorescence spectroscopy, and the obtained data suggested that this molecule might efficiently bind carrier proteins in vivo in order to reach the target site.

New Phenolic Derivatives of Thiazolidine-2,4-dione with Antioxidant and Antiradical Properties: Synthesis, Characterization, In Vitro Evaluation, and Quantum Studies.

Oxidative stress has been incriminated in the physiopathology of many diseases, such as diabetes, cancer, atherosclerosis, and cardiovascular and neurodegenerative diseases. There is a great interest in developing new antioxidants that could be useful for preventing and treating conditions for which oxidative stress is suggested as the root cause. The thiazolidine-2,4-dione derivatives have been reported to possess various pharmacological activities and the phenol moiety is known as a pharmacophore in many naturally occurring and synthetic antioxidants. Twelve new phenolic derivatives of thiazolidine-2,4-dione were synthesized and physicochemically characterized. The antioxidant capacity of the synthesized compounds was assessed through several in vitro antiradical, electron transfer, and Fe2+ chelation assays. The top polyphenolic compounds 5f and 5l acted as potent antiradical and electron donors, with activity comparable to the reference antioxidants used. The ferrous ion chelation capacity of the newly synthesized compounds was modest. Several quantum descriptors were calculated in order to evaluate their influence on the antioxidant and antiradical properties of the compounds and the chemoselectivity of the radical generation reactions has been evaluated. The correlation with the energetic level of the frontier orbitals partially explained the antioxidant activity, whereas a better correlation was found while evaluating the O-H bond dissociation energy of the phenolic groups.