Design, Synthesis and Cytotoxic Activity of Novel Salicylaldehyde Hydrazones against Leukemia and Breast Cancer.

Despite the significant advancements in complex anticancer therapy, the search for new and more efficient specific anticancer agents remains a top priority in the field of drug discovery and development. Here, based on the structure-activity relationships (SARs) of eleven salicylaldehyde hydrazones with anticancer activities, we designed three novel derivatives. The compounds were tested in silico for drug-likeness, synthesized, and evaluated in vitro for anticancer activity and selectivity on four leukemic cell lines (HL-60, KE-37, K-562, and BV-173), one osteosarcomic cell line (SaOS-2), two breast adenocarcinomic cell lines (MCF-7 and MDA-MB-231), and one healthy cell line (HEK-293). The designed compounds were found to have appropriate drug likeness and showed anticancer activities in all cell lines tested; particularly, two of them exhibited remarkable anticancer activity in nanomolar concentrations on the leukemic cell lines HL-60 and K-562 and the breast cancer MCF-7 cells and extraordinary selectivity for the same cancer lines ranging between 164- and 1254-fold. The study also examined the effects of different substituents on the hydrazone scaffold and found that the 4-methoxy salicylic moiety, phenyl, and pyridinyl rings are the most appropriate for anticancer activity and selectivity of this chemical class.

The Phytochemical Profiling, In Vitro Antioxidant, and Hepatoprotective Activity of Prenanthes purpurea L. and Caffeoylquinic Acids in Diclofenac-Induced Hepatotoxicity on HEP-G2 Cells.

Oxidative stress is a common phenomenon of many liver disorders; it both affects patient survival and directly influences the applicability, effectiveness, and toxicity of drugs. In the pursuit of reliable natural remedies for hepatoprotection, this study reports on the complete phytochemical characterization, antioxidant, and hepatoprotective activities of the Prenanthes purpurea methanol-aqueous extract in an in vitro model of diclofenac-induced liver injury (DILI). An ultra high-performance liquid chromatography-high-resolution mass spectrometry analysis (UHPLC-HRMS) was conducted, delineating more than 100 secondary metabolites for the first time in the species, including a series of phenolic acid-hexosides, acylquinic, acylhydroxyquinic and acyltartaric acids, and flavonoids. Quinic acid, chlorogenic, 3,5-dicaffeoylquinic and 5-feruloylhydroxyquinic acid, caffeoyltartaric and cichoric acids, eryodictiol-O-hexuronide, and luteolin O-hexuronide dominated the phytochemical profile and most likely contributed to the observed hepatoprotective activity of the studied P. purpurea leaf extract. The potency and molecular basis of cellular protection were investigated in parallel with pure caffeoylquinic acids in a series of pretreatment experiments that verified the antiapoptotic and antioxidant properties of the natural products.

Fused Triazinobenzimidazoles Bearing Heterocyclic Moiety: Synthesis, Structure Investigations, and In Silico and In Vitro Biological Activity.

[1,3,5]Triazino[1,2-a]benzimidazole-2-amines bearing heterocyclic moiety in 4-position were synthesized. The compounds were characterized by elemental analysis, IR, 1H-NMR, 13C-NMR, and HRMS spectroscopy. The molecular geometry and electron structure of these molecules were theoretically studied using density functional theory (DFT) methods. The molecular structure of the synthesized fused triazinobenzimidazole was confirmed to correspond to the 3,4-dihydrotriazinobenzimidazole structure through the analysis of spectroscopic NMR data and DFT calculations. The antinematodic activity was evaluated in vitro on isolated encapsulated muscle larvae (ML) of Trichinella spiralis. The results showed that the tested triazinobenzimidazoles exhibit significantly higher efficiency than the conventional drug used to treat trichinosis, albendazole, at a concentration of 50 µg/mL. The compound 3c substituted with a thiophen-2-yl moiety exhibited the highest anthelmintic activity, with a larvicidal effect of 58.41% at a concentration of 50 µg/mL after 24 h of incubation. Following closely behind, the pyrrole analog 3f demonstrated 49.90% effectiveness at the same concentration. The preliminary structure-anti-T. spiralis activity relationship (SAR) of the analogues in the series was discussed. The cytotoxicity of the benzimidazole derivatives against two normal fibroblast cells (3T3 and CCL-1) and two cancer human cell lines (MCF-7 breast cancer cells and chronic myeloid leukemia cells AR-230) was evaluated using the MTT-dye reduction assay. The screening results indicated that the compounds showed no cytotoxicity against the tested cell lines. An in silico study of the physicochemical and pharmacokinetic characteristics of the novel synthesized fused triazinobenzimidazoles showed that they were characterized by a significant degree of drug-likeness and optimal properties for anthelmintic agents.

Gallium (III) Complexes with 5-Bromosalicylaldehyde Benzoylhydrazones: In Silico Studies and In Vitro Cytotoxic Activity.

Gallium (III) complexes with the ligands 5-bromosalicylaldehyde-4-hydroxybenzoylhydrazone and 5-bromosalicylaldehyde isonicotinoylhydrazone were synthesized to receive compounds with improved antiproliferative action. Compounds were characterized by elemental analysis, IR, and NMR spectroscopy. Density functional theory calculations with Becke's 3-parameter hybrid functional and 6-31+G(d,p) basis set were carried out to investigate the structural features of the ligands and Ga(III) complexes. Cytotoxic screening by MTT-dye reduction assay was carried out using cisplatin and melphalan as reference cytotoxic agents. A general formula [Ga(HL)2]NO3 for the complexes obtained was suggested. The complexes are mononuclear with the Ga(III) ions being surrounded by two ligands. The ligands acted as monoanionic tridentate (ONO) donor molecules. The analysis revealed coordination binding through deprotonated phenolic-oxygen, azomethine-nitrogen, and amide-oxygen atoms. The bioassay demonstrated that all compounds exhibited concentration-dependent antiproliferative activity at low micromolar concentrations against the acute myeloid leukemia HL-60 and T-cell leukemia SKW-3 cell lines. IC50 values of 5-bromo-derivative ligands and gallium (III) complexes are lower than those of cisplatin and much lower than these of melphalan. The coordination to gallium (III) additionally increased the cytotoxicity compared to the metal-free hydrazones.

Modulation Effect on Tubulin Polymerization, Cytotoxicity and Antioxidant Activity of 1H-Benzimidazole-2-Yl Hydrazones.

1H-benzimidazol-2-yl hydrazones with varying hydroxy and methoxy phenyl moieties were designed. Their effect on tubulin polymerization was evaluated in vitro on porcine tubulin. The compounds elongated the nucleation phase and slowed down the tubulin polymerization comparably to nocodazole. The possible binding modes of the hydrazones with tubulin were explored by molecular docking at the colchicine binding site. The anticancer activity was evaluated against human malignant cell lines MCF-7 and AR-230, as well as against normal fibroblast cells 3T3 and CCL-1. The compounds demonstrated a marked antineoplastic activity in low micromolar concentrations in both screened in vitro tumor models. The most active were the trimethoxy substituted derivative 1i and the positional isomers 1j and 1k, containing hydroxy and methoxy substituents: they showed IC50 similar to the reference podophyllotoxin in both tumor cell lines, accompanied with high selectivity towards the malignantly transformed cells. The compounds exerted moderate to high ability to scavenge peroxyl radicals and certain derivatives-1l containing metha-hydroxy and para-methoxy group, and 1b-e with di/trihydroxy phenyl moiety, revealed HORAC values high or comparable to those of well-known phenolic antioxidants. Thus the 1H-benisimidazol-2-yl hydrazones with hydroxy/methoxy phenyl fragments were recognized as new agents exhibiting promising combined antioxidant and antineoplastic action.

GC-MS analysis of Amaryllidaceae and Sceletium-type alkaloids in bioactive fractions from Narcissus cv. Hawera.

RATIONALE: Narcissus cv. Hawera has been found to biosynthesize some Sceletium-type alkaloids with antidepressant and anxiolytic activities. This ornamental plant has been poorly studied as a source of bioactive alkaloids including some contraversive reports on in vitro and intact plants. In this study, a detailed GC-MS characterization of its alkaloid fractions is presented. METHODS: GC-MS was used for the identification of compounds in the alkaloid fractions. Both underivatized and silylated samples were analyzed simultaneously. Elevated plus maze and tail suspension tests were used to assay the anxiolytic and antidepressant activities. Ellman's and MTT-dye reduction assays were used to evaluate the acetylcholinesterase (AChE) inhibitory and cytotoxicity activities, respectively. RESULTS: Of the 29 alkaloids, 13 of Sceletium-type were detected. Two new alkaloids were identified as 2-oxo-mesembrine and 2-oxo-epi-mesembrenol. Lycorine was found as a major compound (43.5%) in the crude silylated methanol extract. After the elimination of lycorine by pre-crystallization, the major alkaloids were 40.8% 6-epi-mesembranol, 16.2% 6-epi-mesembrenol, and 13.8% sanguinine. This fraction showed anxiolytic and antidepressant-like activities as well as potent AChE inhibitory and antineoplastic activities. CONCLUSIONS: Silylation of the alkaloid fractions from Narcissus cv. Hawera provides better separation, structural information, and improved sensitivity for compounds with two and more hydroxyl groups. The lycorine-free alkaloid fraction shows a great potential for further pharmacological studies.

Tamoxifen Delivery System Based on PEGylated Magnetic MCM-41 Silica.

Magnetic iron oxide containing MCM-41 silica (MM) with ~300 nm particle size was developed. The MM material before or after template removal was modified with NH2- or COOH-groups and then grafted with PEG chains. The anticancer drug tamoxifen was loaded into the organic groups' modified and PEGylated nanoparticles by an incipient wetness impregnation procedure. The amount of loaded drug and the release properties depend on whether modification of the nanoparticles was performed before or after the template removal step. The parent and drug-loaded samples were characterized by XRD, N2 physisorption, thermal gravimetric analysis, and ATR FT-IR spectroscopy. ATR FT-IR spectroscopic data and density functional theory (DFT) calculations supported the interaction between the mesoporous silica surface and tamoxifen molecules and pointed out that the drug molecule interacts more strongly with the silicate surface terminated by silanol groups than with the surface modified with carboxyl groups. A sustained tamoxifen release profile was obtained by an in vitro experiment at pH = 7.0 for the PEGylated formulation modified by COOH groups after the template removal. Free drug and formulated tamoxifen samples were further investigated for antiproliferative activity against MCF-7 cells.

Delineation of proapoptotic signaling of anthracene-shelled M2L4 metallacapsules and their synergistic activity with curcumin in cisplatin-sensitive and resistant tumor cell lines.

Since the introduction of cisplatin into clinical practice a few decades ago, the topic of metal-based drugs has expanded significantly. Recent examples emphasize on metallosupramolecules as an emerging class of compounds with diverse properties. They can trigger unique cellular events in malignant cells or serve as molecular hosts for various biologically active compounds, including anticancer agents. The anthracene-shelled M2L4 coordination nanocapsules under research have already proved very high anticancer potency with remarkable selectivity and lack of cross-resistance. In this study, we provide an oncopharmacological evaluation of the Pt(II)- and Pd(II)-clipped M2L4 nanocapsules; we report a thorough analysis of their synergistic effects in combined treatments with the pleiotropic anticancer agent curcumin. We examined changes in cellular expression of several apoptosis-related proteins in a panel of tumor cell lines with different chemosensitivity towards cisplatin, i.e. HT-29, HL-60 and its resistant strains HL-60/CDDP and HL-60/Dox, in order to assess the molecular mechanisms of their antitumor activity The results of the immunoassay concluded activation of the mitochondrial apoptotic pathway in all the screened tumor lines. A prevalent modulation of the extrinsic apoptotic signaling cascade was observed in the chemoresistant variants. Curcumin interactions of the tested compounds were estimated against the cisplatin-refractory cell line HT-29 via the Chou-Talalay method (CTM), whereby the palladium species yielded superior synergistic activity as compared to their platinum analogues.

Cellular Pharmacology of Palladinum(III) Hematoporphyrin IX Complexes: Solution Stability, Antineoplastic and Apoptogenic Activity, DNA Binding, and Processing of DNA-Adducts.

Two paramagnetic PdIII complexes of hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp), namely a dinuclear one [PdIII2(Hp-3H)Cl3(H2O)5]·2PdCl2, Pd1 and a mononuclear metalloporphyrin type [PdIII(Hp-2H)Cl(H2O)]·H2O, Pd2 have been synthesized reproducibly and isolated as neutral compounds at different reaction conditions. Their structure and solution stability have been assayed by UV/Vis and EPR spectroscopy. The compounds researched have shown in vitro cell growth inhibitory effects at micromolar concentration against a panel of human tumor cell lines. A DNA fragmentation test in the HL-60 cell line has indicated that Pd1 causes comparable proapoptotic effects with regard to cisplatin but at substantially higher concentrations. Pd1 and cisplatin form intra-strand guanine bis-adducts as the palladium complex is less capable of forming DNA adducts. This demonstrates its cisplatin-dissimilar pharmacological profile. The test for efficient removal of DNA-adducts by the NER synthesis after modification of pBS plasmids with either cisplatin or Pd1 has manifested that the lesions induced by cisplatin are far better recognized and repaired compared those of Pd1. The study on the recognition and binding of the HMGB-1 protein to cisplatin or Pd1 modified DNA probes have shown that HMG proteins are less involved in the palladium agent cytotoxicity.

Synthesis, antimycobacterial activity and docking study of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives and related hydrazide-hydrazones.

A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b-g and coumarin containing hydrazide-hydrazone analogues 4a-e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28-1.69µM, which were comparable to those of isoniazid. The cytotoxicity (IC50>200µM) to the "normal cell" model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b-e, was noticeably milder compared to that of their hydrazone analogues 4a-e (IC50 33-403µM). Molecular docking studies on compounds 4a-e and 5b-g were also carried out to investigate their binding to the 2-trans-enoyl-ACP reductase (InhA) enzyme involved in M. tuberculosis cell wall biogenesis. The binding model suggested one or more hydrogen bonding and/or arene-H or arene-arene interactions between hydrazones or pyrazole-fused coumarin derivatives and InhA enzyme for all synthesized compounds.

Antimycobacterial activity of novel hydrazide-hydrazone derivatives with 2H-chromene and coumarin scaffold.

This study reports the synthesis of new 2H-chromene or coumarin based acylhydrazones, which were evaluated for their in vitro antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and compared to the first-line antituberculosis drugs, isoniazid (INH) and ethambutol (EMB). The most active compounds 7m (MIC 0.13µM), 7o (MIC 0.15µM) and 7k (MIC 0.17µM) demonstrated antimycobacterial activity at submicromolar concentration level and remarkably minimal associated cytotoxicity in the human embryonic kidney cell line HEK-293T. Structure-activity relationship for this class of compounds has been established.

HPLC-UV and LC-MS Analyses of Acylquinic Acids in Geigeria alata (DC) Oliv. & Hiern. and their Contribution to Antioxidant and Antimicrobial Capacity.

INTRODUCTION: Geigeria alata is a traditional plant used in Sudanese folk medicine for treatment of diabetes, cough, epilepsy and intestinal complaints. OBJECTIVE: To analyze phenolic acids in Geigeria alata roots and leaves and to evaluate their antioxidant and antimicrobial activities. METHODOLOGY: Phenolic acids in the aqueous-methanol extracts were identified by LC-MS. Major compounds were isolated using low-pressure liquid chromatography. The quantitative analysis of phenolic acids was performed by a validated HPLC-UV method with limits of detection ranging from 0.04 to 0.57 µg/mL. 2,2-Diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazine-6-sulphonic acid) (ABTS) and ferric reducing antioxidant power (FRAP) methods were used for antioxidant activity evaluation. In addition, the minimal inhibitory concentration and the minimal bactericidal concentration against a panel of pathogenic bacteria and fungi were determined by the broth microdilution test. RESULTS: For the first time protocatechuic, caffeic, p-coumaroylquinic, caffeoylsinapoylquinic, caffeoylferuloylquinic, three feruloylquinic, six caffeoylquinic acids, and a caffeic acid hexoside were detected in Geigeria alata roots by LC-MS. HPLC-UV analyses showed that 3,5-dicaffeoylquinic acid (25.96 ± 2.08 mg/g dry weight (DW)) was the most abundant phenolic acid in roots, while 4,5-dicaffeoylquinic acid (8.99 ± 0.56 mg/g DW) was the main compound present in leaves. 3,5-Dicaffeoylquinic acid demonstrated stronger radical scavenging activity and reducing power compared with the crude extracts and the positive control 5-caffeoylquinic acid. 3,4,5-Tricaffeoylquinic acid revealed the highest antibacterial potential against the penicillin sensitive and resistant Staphylococcus aureus strains, as well as methicillin-resistant S. aureus. CONCLUSION: The caffeoylquinic acids content of up to 6.22% in Geigeria alata roots establishes this species as a new source rich in these bioactive molecules. Copyright © 2016 John Wiley & Sons, Ltd.

Partially Hydrolyzed Poly(n-propyl-2-oxazoline): Synthesis, Aqueous Solution Properties, and Preparation of Gene Delivery Systems.

Random copolymers of n-propyl-2-oxazoline and ethylenimine (PPrOx-PEI) were prepared by partial acidic hydrolysis of poly(n-propyl-2-oxazoline) (PPrOx). Dynamic and electrophoretic light scattering and diffusion-ordered NMR spectroscopy were utilized to investigate aqueous solution properties of the copolymers. Above a specific cloud point temperature, well-defined nanoparticles were formed. The latter consisted of a core composed predominantly of PPrOx and a thin positively charged shell from PEI moieties that mediated formation of polyplexes with DNA. The polyplexes were prepared at 65 °C at varying N/P (amine-to-phosphate groups) ratios. They underwent structural changes upon temperature variations 65-25-37 °C depending on N/P. At N/P < 2, the polyplex particles underwent minor changes because of formation of a surface layer of DNA that acted as a barrier and prevented swelling and disintegration of the initial particles. Dramatic rearrangements at N/P ≥ 2 resulting in large swollen microgel particles were overcome by coating of the polyplex particles with a cross-linked polymeric shell. The shell retained the colloidal stability and preserved the physicochemical parameters of the initial polyplex particles while it reduced the high surface potential values. Progressive loss of cytotoxicity upon complexation with DNA and coating of polyplex particles was displayed.

Synthesis and antimycobacterial activity of novel camphane-based agents.

A series of six new amidoalcohols was designed and synthesized on the base of the camphor scaffold. Natural amino acids were transformed into their α-hydroxy analogues with retention of configuration, and attached to isobornylamine. The compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. The activity shifts from micromolar to nanomolar inhibitory concentrations depending on the α-hydroxy acid moiety. Two of the most potent compounds exert low level of cytotoxic activity. These camphane-based amido-alcohols present promising potential lead compounds for further elaboration of antimycobacterial agents.

Theophylline-7-acetic acid derivatives with amino acids as anti-tuberculosis agents.

A series of amides were synthesized by condensation of theophylline-7-acetic acid and eight commercially available amino acid methyl ester hydrochlorides. Consecutive hydrolysis of six of the amido-esters resulted in the formation of corresponding amido-acids. The newly synthesized compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. The activity varied depending on the amino acid fragments and in seven cases exerted excellent values with MICs 0.46-0.26 µM. Assessment of the cytotoxicity revealed that the compounds were not cytotoxic against the human embryonal kidney cell line HEK-293T. The theophylline-7-acetamides containing amino acid moieties appear to be promising lead compounds for the development of antimycobacterial agents.

pH-responsive niosome-based nanocarriers of antineoplastic agents.

Differences in pH between the tumour interstitium and healthy tissues can be used to induce conformational changes in the nanocarrier structure, thereby triggering drug release at the desired site. In the present study, novel pH-responsive nanocarriers were developed by modifying conventional niosomes with hexadecyl-poly(acrylic acid)n copolymers (HD-PAAn). Niosomal vesicles were prepared by the thin film hydration method using Span 60, Span 60/Tween 60 and cholesterol as main constituents, and HD-PAA modifiers of different concentrations (0.5, 1, 2.5, 5 mol%). Next, two model substances, a water-soluble fluorescent dye (calcein) and a hydrophobic agent with pronounced antineoplastic activity (curcumin), were loaded in the aqueous core and hydrophobic membrane of the elaborated niosomes, respectively. Physicochemical properties of blank and loaded nanocarriers such as hydrodynamic diameter (Dh), size distribution, zeta potential, morphology and pH-responsiveness were investigated in detail. The cytotoxicity of niosomal curcumin was evaluated against human malignant cell lines of different origins (MJ, T-24, HUT-78), and the mechanistic aspects of proapoptotic effects were elucidated. The formulation composed of Span 60/Tween 60/cholesterol/2.5% HD-PAA17 exhibited optimal physicochemical characteristics (Dh 302 nm; ζ potential -22.1 mV; high curcumin entrapment 83%), pH-dependent drug release and improved cytotoxic and apoptogenic activity compared to free curcumin.

Protective effect of Aronia melanocarpa fruit juice in a model of cisplatin-induced cytotoxicity in vitro.

AIM: The aim of the present study was to investigate the protective potential of Aronia melanocarpa fruit juice in a model of cisplatin-induced cytotoxicity in the human embryonal kidney cell line HEK293T. MATERIALS AND METHODS: The cellular viability was assessed using the MTT-dye reduction assay based on the reduction of the yellow tetrazolium dye MTT to a violet formazan product via the mitochondrial succinate dehydrogenase in viable cells. Cisplatin was applied in various concentrations either alone or after a 24-hour pretreatment of the cells with Aronia melanocarpa fruit juice at 0.1 and 0.05 mg/ml. The half maximal inhibitory concentrations (IC50 values) were derived from the concentration-response curves to cisplatin. RESULTS: Applied alone, the anticancer drug caused a prominent decrease of cellular viability with IC50 8.3 +/- 1.1 microM. The juice proved to significantly ameliorate the in vitro cytotoxicity of the platinum drug, in a concentration-dependent manner. The pretreatment of the cells with Aronia melanocarpa fruit juice resulted in a significant increase (p < 0.001) of IC50 for cisplatin to 25.1 +/- 2.7 microM (at 0.05 mg/ml) and 34.4 +/- 3.4 microM (at 0.1 mg/ml), respectively. CONCLUSION: The protective effect of Aronia melanocarpa fruit juice observed in this study is most probably due to its well appreciated antioxidant activity as oxidative stress plays a central role in the toxic effects of cisplatin.

Pharmacological Activities of Schiff Bases and Their Derivatives with Low and High Molecular Phosphonates.

This review paper is focused on the design of anthracene and furan-containing Schiff bases and their advanced properties as ligands in complex transition metal ions The paper also provides a brief overview on a variety of biological applications, namely, potent candidates with antibacterial and antifungal activity, antioxidant and chemosensing properties. These advantageous properties are enhanced upon metal complexing. The subject of the review has been extended with a brief discussion on reactivity of Schiff bases with hydrogen phosphonates and the preparation of low and high molecular phosphonates, as well as their application as pharmacological agents. This work will be of interest for scientists seeking new challenges in discovering advanced pharmacological active molecules gaining inspiration from the versatile families of imines and aminophosphonates.

Nationwide analysis of the impact of COVID-19 in patients with a cardiovascular, oncological or chronic pulmonary disease in the context of an Eastern European country with a low vaccination rate, Bulgaria: March 2020-April 2022.

OBJECTIVE: This study focused on Bulgarian patient cohorts harbouring a single documented chronic comorbidity-cardiovascular pathology, an oncological disease or a chronic pulmonary diseases (CPD) comparing the outcomes in fully vaccinated and non-vaccinated populations classified by sex and age groups in ambulatory, hospital and intensive care unit (ICU) settings at the national level. DESIGN: Retrospective analysis SETTINGS, PARTICIPANTS AND OUTCOME MEASURES: In total, 1 126 946 patients with confirmed COVID-19, on a national level, were retrospectively analysed between March 2020 and April 2022, using data from the Ministry of Health's United Information Portal, launched in March 2020. RESULTS: Of all the confirmed 247 441 hospitalised cases of COVID-19, 67 723 (27.3%) had documented cardiovascular disease (CVD), 2140 (0.9%) had confirmed solid malignancy (regardless of stage) and 3243 (1.3%) had established CPD as their only chronic pathology. The number of cumulative deaths in each subgroup was 10 165 (in-hospital=5812 and ICU=4353); 4.0% vaccinated (410/10 165, p<0.001), 344 (in-hospital=196 and ICU=148), 4.9% vaccinated (17/344, p<0.001), 494 (in-hospital=287 and ICU=207) and 5.2% vaccinated (26/494, p<0.001), respectively. Statistical significance (p<0.001) was obtained in favour of reduced ambulatory, hospitalisation and both in-hospital and ICU-related mortality in the vaccinated cohorts, and BNT162b2 was the most effective at preventing mortality in all age groups. CONCLUSIONS: This retrospective analysis shows that patients vaccinated against COVID-19 demonstrated trends of reduced hospitalisations and premature mortality in patients with CVD, solid malignancy or CPD as a single comorbidity.

Ferrocene modified analogues of imatinib and nilotinib as potent anti-cancer agents.

The unique features of ferrocene and the need for development of targeted anticancer drugs inspired the design, synthesis and biological evaluation of ferrocenyl modified tyrosine kinase inhibitors by replacing the pyridyl moiety in imatinib and nilotinib generalized structures with a ferrocenyl group. A series of seven new ferrocene analogues were synthesized and evaluated for their anticancer activity in a panel of bcr-abl positive human malignant cell lines using imatinib as a reference drug. The metallocenes exhibited a dose-dependent inhibition on malignant cell growth with varying antileukemic activity. The most potent analogues were compounds 9 and 15a showing comparable or even superior efficacy to the reference. Their cancer selectivity indices suggest a favorable selectivity profile, indicating a 250 times higher preferential activity of 15a towards malignantly transformed K-562 cells and an even twice greater one (500) of 9 in the LAMA-84 leukemic model as compared to the normal murine fibroblast cell line.