Elimination Of Acid Research Articles

Nucleophilic Dearomatization of Activated Pyridines Using Vinyl Sulfoxonium Ylides: Application to the Synthesis of Bis-Heterocycles.

A highly efficient method has been developed for synthesizing 4-dienyl dihydropyridines through the nucleophilic dearomatization of activated pyridines using vinyl sulfoxonium ylides. This reaction follows the sequence involving ylide addition to activated pyridine, [2,3]-sigmatropic rearrangement, and subsequent sulfenic acid elimination. The resulting 4-dienyl dihydropyridines are then used in the synthesis of highly substituted bis-heterocyles. Control experiments and quantum chemical calculations were conducted to elucidate the selectivity and the mechanistic pathway.

Synthesis of tricarbonylated propargylamine and conversion to 2,5-disubstituted oxazole-4-carboxylates.

The N,O-acetal derived from diethyl mesoxalate (DEMO) undergoes elimination of acetic acid upon treatment with a base, leading to the formation of N-acylimine in situ. Lithium acetylide readily attacks the imino group to afford N,1,1-tricarbonylated propargylamines. When the resulting propargylamine reacts with butyllithium, ring closure occurs between the ethynyl and carbamoyl groups, yielding 2,5-disubstituted oxazole-4-carboxylates. This cyclization also occurs when the propargylamine is heated with ammonium acetate, resulting in double activation.

Stem cell seeding of decellularised porcine right ventricular outflow tracts to advance repair of congenital heart defects

Abstract Background Replacement of the right ventricular outflow tract (RVOT) is necessary in many critical congenital heart disease subtypes, often when the child is less than one year old. Poor availability of small-diameter cardiac homografts necessitates the use of xenografts in paediatric surgical reconstruction. Currently used xenografts are limited by immunoincompatibility and lack of growth, requiring repeat surgery to replace the defective graft. One approach to tackle acute immune rejection of animal tissue is aldehyde fixation of grafts prior to xenotransplantation. Though masking antigenicity, fixation is associated with multiple issues, including toxicity of fixative remnants and calcification. Decellularisation of biological grafts to remove foreign material is a promising alternative to reduce immunogenicity and dampen the risk of rejection. To combat lack of growth, in vitro cellularisation with stem cells is a promising solution. Purpose Current RVOT substitutes have not proven to be a lifelong solution for paediatric cardiac repair. This research has optimised a novel decellularisation technique for porcine RVOTs to produce a durable and cell-free scaffold with translational capability. Current work is looking to seed mesenchymal stem cells (MSCs) onto the acellular RVOT in vitro to enhance immune tolerance and endow the graft with growth capacity upon implant. Methods First, this decellularisation technique produces acellular RVOT scaffolds by simultaneously utilising three methods: enzymatic, chemical, and mechanical decellularisation. Novel to this method, the latter is realised using a 3D printed flow chamber to utilise the shear forces of continuous fluid flow for cell removal from the external and internal RVOTs structure. Coating the acellular graft with poly-lysine has then enabled recellularisation with MSCs isolated from the umbilical cord. Results Nuclei quantification demonstrates decellularisation of all structures of the RVOT, and elimination of residual nucleic acids is evidenced. Immunohistochemical analysis confirms the xenoantigen Galα1-3Galβ1-4GlcNAc-R is absent from the decellularised tissue. In parallel with removal of typical immunogens associated with the rejection response, the elastin and collagen fibres of the extracellular matrix are maintained, supported by histology and electron microscopy. Importantly, the tensile properties of the decellularised grafts are preserved. Finally, MSCs adhered onto the external pulmonary artery surface in vitro, achieving a uniform monolayer of cells. Conclusion RVOTs have been successfully decellularised and proven to possess seeding potential. Future work aims to characterise the seeded MSCs to assess parameters including proliferative capacity and expression of typical MSC markers. Overall, this work has the potential to produce a non-immunogenic graft possessing growth potential as a surgical alternative for paediatric RVOT replacement.

Steered molecular dynamics simulation as a post-process to optimize the iBRAB-designed Fab model.

Therapeutic monoclonal antibodies are an effective method of treating acute infectious diseases. However, knowing which of the produced antibodies in the vast number of human antibodies can cure the disease requires a long time and advanced technology. The previously introduced iBRAB method relies on studied antibodies to design a broad-spectrum antibody capable of neutralizing antigens of many different Influenza A viral strains. To evaluate the antigen-binding fragment as an applicable drug, the therapeutic antibody profiles providing guidelines collected from clinically staged therapeutic antibodies were used to access different measurements. Although the evaluated values were within an accepted range, the modification in the amino acid sequence is required for better properties. Thus, using the steered molecular dynamics(SMD) simulation to determine the binding capacity of amino acids in the functional region, the profile of interacted amino acids of Fab with the antigen was established for modified reference. As a result, the model was modified with amino acids elimination at positions 96-97 in the heavy chain and 26-27, 91, 96-97, and 102-103 in the light chain, which has better Therapeutic Antibody Profiler evaluations than the original designation. Thus again, SMD simulation is a promising computational approach for post-modification in rational drug design.

Elimination of industrial Trans Fatty Acids from the food supply chain: With a focus on India

With the growing health concerns of Industrial Trans Fatty Acids (i-TFAs) present in food, efforts are being made to eliminate these Trans Fatty Acids (TFAs) from food chain. Even after three decades of research which linked the i-TFAs and human health, getting rid of these from food supply chain is still a dream for major countries around the globe. Countries are struggling hard to convey the related scientific findings to the common public aiming to eliminate i-TFAs from food supply chain. Government and non-government organisations throughout the globe have implemented several regulatory measures to get rid of the Industrial i-TFAs from the diet. In the case of India, removing these TFAs from the food supply chain would need a multi-sectoral, proactive effort at the consumer and production levels. The paper aims to assess and give an overview of the i-TFAs to critically analyse the elimination efforts of i-TFAs from the dietary supply chain with a focus on India. The obstacles and challenges in the elimination process of industrial Trans Fatty acids from food chain are discussed which are relevant to the developing countries like India.

New Biomarkers for Renal Transporter-Mediated Drug-Drug Interactions: Metabolomic Effects of Cimetidine, Probenecid, Verapamil, and Rifampin in Humans.

The inhibition of renal transport proteins organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1, MATE2-K), and organic anion transporters (OAT1, OAT3) causes clinically relevant drug-drug interactions (DDI). Endogenous biomarkers could be used to improve risk prediction of such renal DDIs. While a number of biomarkers for renal DDIs have been described so far, multiple criteria for valid biomarkers have frequently not been investigated, for example, specificity, metabolism, or food effects. Therefore, there is a need for novel biomarkers of renal DDIs. Here, we investigated the global metabolomic effects following the administration of two classical inhibitors of renal transport proteins [cimetidine (OCT2/MATEs), probenecid (OATs)] in human plasma and urine of healthy volunteers. Additionally, we investigated metabolomic effects of two inhibitors of other transporters [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides)] as controls. This analysis shows that both cimetidine and probenecid affect compounds involved in caffeine metabolism, carnitines, and sulfates. Hierarchical cluster analysis of the effects of all four inhibitors on endogenous compounds identified multiple promising new sensitive and specific biomarker candidates for OCT2/MATE- or OAT-mediated DDIs. For OCT2/MATEs, 5-amino valeric acid betaine (median log2-fold change of estimated renal elimination: -3.62) presented itself as a promising candidate. For OATs, estimated renal elimination of 7-methyluric acid and cinnamoylglycine (median log2-fold changes -3.10 and -1.92, respectively) was both sensitive and specific. This study provides comprehensive information on metabolomic effects of transport protein inhibition in humans and identifies putative new sensitive and specific biomarkers for renal transporter-mediated DDIs.

Preparation of Neptunyl and Plutonyl Acetates To Access Nonaqueous Transuranium Coordination Chemistry.

Uranyl diacetate dihydrate is a useful reagent for the preparation of uranyl (UO22+) coordination complexes, as it is a well-defined stoichiometric compound featuring moderately basic acetates that can facilitate protonolysis reactivity, unlike other anions commonly used in synthetic actinide chemistry such as halides or nitrate. Despite these attractive features, analogous neptunium (Np) and plutonium (Pu) compounds are unknown to date. Here, a modular synthetic route is reported for accessing stoichiometric neptunyl(VI) and plutonyl(VI) diacetate compounds that can serve as starting materials for transuranic coordination chemistry. The new NpO22+ and PuO22+ complexes, as well as a corresponding molecular UO22+ complex, are isomorphous in the solid state, and in solution show similar solubility properties that facilitate their use in synthesis. In both solid and solution state, the +VI oxidation state (O.S.) is maintained, as demonstrated by vibrational and optical spectroscopy, confirming that acetate anions stabilize the oxidizing, high-valent +VI states of Np and Pu as they do for the more stable U(VI). All three acetate salts readily react with a model diprotic ligand, affording incorporation of U(VI), Np(VI), and Pu(VI) cores into molecular coordination compounds that occurs concomitantly with elimination of acetic acid; the new complexes are high-valent, yet overall charge neutral, facilitating entry into nonaqueous chemistry by rational synthesis. Computational studies reveal that the dianionic ligand framework assists in stabilizing the +VI O.S. via donation to the 5f shells of the actinides, highlighting the potential usefulness of protonolysis reactivity toward preparation of stabilized high-valent transuranic species.

Cascade Synthesis of Pyrrolo[1,2-a]quinolines and Pyrrolo[2,1-a]isoquinolines via Formal [3 + 2]-Cycloaddition of Push-Pull Nitro Heterocycles with Carbonyl-Stabilized Quinolinium/Isoquinolinium Ylides.

Various substituted pyrrolo[1,2-a]quinolines and pyrrolo[2,1-a]isoquinolines were synthesized in good to high yields by the Et3N-mediated reaction of push-pull 3-nitrobenzofurans or 1-Ts-/1-Ms-3-nitroindoles and precursors of carbonyl-stabilized quinolinium and isoquinolinium ylides as 1,3-dipole equivalents. These transformations proceed in a one-pot manner starting with the formal [3 + 2]-cycloaddition stage, which is accompanied by double dearomatization of both quinoline/isoquinoline and benzofuran/indole moieties, followed by ring-opening of cyclic intermediate formed and nitrous acid elimination sequence. [3 + 2]-Cycloadducts were isolated as the final products in cases of impossibility or difficulty of their enolization. The present protocol was successfully extended to 3-nitro-4H-chromene derivatives as push-pull dipolarophile component. Finally, using the method of competing reactions, the reactivity of the starting compounds was compared with each other.

Light-enhancing ketone transfer hydrogenation catalyzed by diphosphine phenanthroline ruthenium complexes

The cationic phenanthroline ruthenium derivatives [Ru(OAc)(dppb)(NN)]OAc (NN = phen 1, imidazo[4,5-f][1,10]phenanthroline 2) have been obtained in high yield by reaction of the acetate [Ru(OAc)2dppb] with the corresponding NN ligand. The dinuclear cyclometalated [(dppb)(η2-OAc)(Ru(µ-NN-phenimid-NC)Ru(η2-OAc)(dppb)]OAc (3) has been prepared from 2 with [Ru(OAc)2(dppb)] via elimination of acetic acid. The characterization of these compounds has been carried out by NMR, FT-IR, UV–Vis, conductivity and cyclic voltammetry measurements. These derivatives display catalytic activity in the transfer hydrogenation of aromatic and aliphatic cyclic ketones at S/C up to 2000 in presence of NaOiPr in 2-propanol. An increase of the rate (up to 8 times) has been observed upon irradiation at 30 and 60 °C (300 W Xenon Arc Lamp light source). Control experiments show that [Ru(OiPr)2(dppb)(phen)] (1A), formed from 1 by substitution of the acetate with the isopropoxide ligand, shows a stronger emission compared to 1 and that 1A is quenched by NaOiPr, affording the dihydride [Ru(H)2(dppb)(phen)] (1C) via a photo induced β-H elimination.

The enhanced photocatalytic peroxymonosulfate activation for 2, 4-dichlorophenoxyacetic acid degradation over Z-scheme PTCDA/MIL-88A(Fe) under visible light

To attain significant synergy between adsorption and peroxymonosulfate (PMS) activation for the 2, 4-dichlorophenoxyacetic acid (2, 4-D) elimination, 3, 4, 9, 10-perylenetetracarboxylic dianhydride (PTCDA)/MIL-88A(Fe) (PTxMy) composites were constructed by the facile ball-milling. The adsorption capacity of PT25M175 toward 2, 4-D was calculated as 76.0 mg/g at 308 K based on the Langmuir models. The decomposition of 2, 4-D in PT25M175/Vis/PMS system was investigated through a synergic action of adsorption and photocatalytic PMS activation, in which the optimum PT25M175 composite exhibited the 2, 4-D elimination efficiency up to 98.4 % within 10.0 min. The 2, 4-D degradation was mostly contributed by singlet oxygen (1O2) and superoxide radicals (O2•−), in which non-radical 1O2 accounts for a preponderant oxidation contribution (90.6 %). Based on LC-MS analysis, DFT computation, ecotoxicity analysis, and phytotoxicity evaluation, the 2, 4-D breakdown routes and the toxicity assessment of the degradation products were suggested. The elimination efficiency could be maintained at 97.9 % after five rounds of catalytic experiments. This study provided some guidance for compositing semiconductors with MOFs and utilizing a significant synergistic effect between adsorption and photocatalytic PMS activation to degrade organic pollutants.

Harnessing the potential of cube-like Holmium doped bismuth niobate (Ho–Bi5Nb3O15) amalgamated with rGO sheets for rapid photocatalytic elimination of crystal violet and acetylsalicylic acid

Synthesis of unique morphologies in photocatalytic materials, coupled with utilization of wide-spectrum solar energy through rare earth doping, holds significant promise to maximize the potential of photocatalysts. Herein in, cube-like Holmium (Ho) doped Bi5Nb3O15 was synthesized by the hydrothermal method and integrated with reduced graphene oxide (rGO) sheets. As synthesized Ho–Bi5Nb3O15@rGO composite along its analogs i.e., Bi5Nb3O15 and Ho–Bi5Nb3O15 was characterized by XRD, SEM, FT-IR, TGA, I–V, EIS, Mott-Schottky and photo-current measurements. Phase studies showed that crystallite size for Bi5Nb3O15, Ho–Bi5Nb3O15, and Ho–Bi5Nb3O15@rGO was 27.4, 25.5, and 13.5 nm, respectively. Optical analysis exhibited a reduction in the band gap in consequent to Ho doping from 2.54 to 2.19 eV for Ho–Bi5Nb3O15. Conductivity and photo-current measurements showed a remarkable increase in both electrical conductivity and photo-response of Ho–Bi5Nb3O15 upon its incorporation into rGO matrix, reaching maximum values of 1.72 × 10−2 S/m and 0.66 μA, respectively. The enhanced photocatalytic activity of Ho–Bi5Nb3O15@rGO was ensured through the outstanding photo-degradation efficiency (96.5 %) against crystal violet (CV), greater than Bi5Nb3O15 (49 %) and Ho–Bi5Nb3O15 (63.4 %). Additionally, Ho–Bi5Nb3O15@rGO showed sufficient potential towards the degradation of acetylsalicylic acid (ASA) with 79.1 % photo-degradation. This elevated photocatalytic activity of Ho–Bi5Nb3O15@rGO is believed to be contributed by the collaborative outcomes aroused from the Ho-doping and heterojunction fabrication among cubical Ho–Bi5Nb3O15 and rGO sheets. Hence, our work proposes an efficient strategy for the development of innovative photolytic materials for sustainable wastewater remediation.

ADVANCEMENTS IN UNDERSTANDING THE MOLECULAR MECHANISMS REGULATING URIC ACID METABOLISM IN THE INTESTINE

This review provides contemporary insights into the direct and indirect pathogenetic connections between purine compound metabolism and biochemical processes within the cells of the gastrointestinal system. A thorough analysis of recent publications from 2000 to 2024, sourced from databases including Scopus, PubMed, eLIIBRARY, and Google Scholar, was conducted. Uric acid serves as the end product of purine-containing compound catabolism. Its concentration is intricately regulated through the collaboration of the kidneys and gastrointestinal organs, namely the small intestine and liver. Gout, a chronic condition, emerges from the interplay between molecular genetic factors and external influences. Elevated levels of urates in the blood serum (hyperuricemia) and the deposition of sodium urate crystals in organs and tissues set off a cascade of inflammatory and fibrotic processes within mucosal, smooth muscle, parenchymal, and endothelial cells, including those within the gastrointestinal tract. Normally, a person excretes about 1.5 g of uric acid per day. Under physiological conditions, two-thirds of uric acid is excreted from the body by the kidneys, one-third through the intestines, and a small part is excreted with bile. The hypothesis that links the pathogenesis of hyperuricemia with “renal overload” suggests that the disease may develop as a result of impaired renal excretion with insufficient elimination of uric acid through the intestines. Part of uric acid transport systems actively works in hepatocytes and enterocytes, which determines its formation and clearance. Uric acid transporter proteins are divided into two categories: urate reabsorption transporters and urate excretion transporters, their expression is regulated by transcription factors, hormones and metabolites of intestinal microflora. The influence of intestinal microbiota on uric acid metabolism is related to its participation in purine metabolism, decomposition and elimination of uric acid with metabolites of intestinal flora and inhibition of gouty inflammation and is evaluated as a new therapeutic potential in gout and hyperuricemia, which allows to avoid kidney damage and urolithiasis.

Application of Sublimation in the Synthesis and Crystal Growth of Organosulfones.

The solvent-free elimination of sulfinic acid and aromatization of 1,6-trans-substituted bis(arylsulfone) trienes is reported. It is shown that sublimation can be used as a 'green' method to combine the thermal transformation of six trienes and the crystal growth of the resulting 4-(phenylsulfonyl)biphenyls. When the sublimation conditions are carefully controlled, high quality single crystals of the 4-(phenylsulfonyl)biphenyls are obtained. Theoretical modelling of the reaction using the simplified triene Ph-(CH)6-SO2H showed that the cyclization is energetically feasible and that the complete conversion is possible during the timescale of the sublimation. At temperatures slightly higher than the optimum sublimation temperature two of the trienes transformed into 1,4-cyclohexadienes that did not eliminate phenylsulfinic acid. A reaction mechanism involving a 1,3-hydrogen shift induced by free PhS• radicals is proposed for the formation of the 1,4-cyclohexadienes.

Iodination of Substituted Alkynes in the Presence of Cadmium(II) Acetate

AbstractA convenient and selective method for the preparation of substituted iodoalkynes, iodoalkenes based on the interaction of propargylic compounds with iodine in the presence of readily available cadmium (II) acetate in some solvents was developed. The highest yields of iodoalkynes and iodoalkenes were recorded using DMSO as the solvent. An excess of the alkylpropargyl substrate unambiguously led to iodolkynes. By varying the reaction conditions using a twofold excess of iodine in DMSO, methanol or ethanol it was possible to achieve a one‐pot preparation of triiodoalkenes. The interaction of iodine with propargyl substrates could be represented in two ways: formation and further nucleophilic transformation of the iodonium complex under the influence of the acetate ion and generation of π‐coordinated species and elimination of acetic acid.

Flash vacuum pyrolysis of steroid esters

We report here our synthetic approach to acetylenic esters of six different steroids. The use of flash vacuum pyrolysis (FVP) is a very appealing tool for the acetylenic moiety to efficiently cyclize and rearrange which allows access to medicinally and pharmaceutically valuable products. Each substrate was subjected to FVP. The products were analyzed, identified and characterized. Acetylenic esters of aromatic steroids resulted in 2H-cyclohepta[b]furan-2-one, and 2H-chromen-2-one derivatives, while aliphatic esters afforded unsaturated polycyclic hydrocarbons via elimination of propiolic acid.

Conditions and Mechanism of Formation of the Maillard Reaction Pigment, Furpenthiazinate, in a Model System and in Some Acid Hydrolyzates of Foods and its Biological Properties.

Furpenthiazinate is a yellow pigment formed by the Maillard reaction between cysteine and furfural under strongly acidic conditions. Here, we describe the conditions and mechanism of pigment formation in a model system and in an acid hydrolyzate of food and analyze its biological properties. A reaction solution containing 32 mM cysteine and 128 mM furfural or 64 mM cysteine and 256 mM furfural in the presence of 2-6 M hydrochloric acid that was heated to 110 °C for 1-2 h yielded approximately 3 mM furpenthiazinate. Nuclear magnetic resonance analysis of furpenthiazinate prepared using 1-13C or 5-13C d-ribose suggests that it was formed through the condensation of cysteine and two C5 chains derived from pentose with the dehydration and elimination of formic acid. Furpenthiazinate was detected in mieki, a seasoning, and some acid hydrolyzates of food, and it did not show antibacterial or mutagenic activity.

Hepatobiliary circulation and dominant urinary excretion of homogentisic acid in a mouse model of alkaptonuria.

Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type 1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in bile in AKU (mean [±SD] = 1003[±410] μmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] μmol/L). Biliary tyrosine, 3(4-hydroxyphenyl)pyruvic acid (HPPA) and 3(4-hydroxyphenyl)lactic acid (HPLA) are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion. These data provide new insights into pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. We propose that our finding of approximately 3.8 times greater urinary HGA excretion in AKU mice compared with patients is one reason for the lack of extensive tissue ochronosis in the AKU mouse model.

Rapid Synthesis of 3-Methyleneisoindolin-1-ones via Metal-Free Tandem Reactions of Ester-Functionalized Aziridines.

We have disclosed a novel metal-free tandem cyclization reaction for the synthesis of 3-methyleneisoindolin-1-ones starting from ester-functionalized aziridines. This strategy can be effectively promoted by DBU and carboxylic acids. Mechanistically, it involves sequential ring opening of aziridines with carboxylic acids, lactamization, and elimination of carboxylic acids.

Reactions of 1-amino-2-nitroguanidine with 3-nitroacrylates

The reactions of 1-amino-2-nitroguanidine with 3-nitro- acrylates afford aza-Michael adducts. The latter when refluxed in an aqueous alkaline medium undergo elimination of nitrous acid followed by shift of the resulting C=C bond into C=N position giving finally N-substituted alkylpyruvate hydrazones. These compounds can also be prepared in a one-pot procedure; NMR spectroscopy and X-ray diffraction analysis confirmed the existence of the obtained hydrazones as E-isomers.

A Homodimer of Withaferin A Formed by Base-Promoted Elimination of Acetic Acid from 27-O-Acetylwithaferin A Followed by a Diels-Alder Reaction.

Treatment of 27-O-acetylwithaferin A (2) with the non-nucleophilic base, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), afforded 5β,6β-epoxy-4β-hydroxy-1-oxo-witha-2(3),23(24),25(27)-trienolide (3) and 4, a homodimer of withaferin A resulting from a Diels-Alder [4 + 2] type cycloaddition of the intermediate α,β-dimethylene-δ-lactone (9). Structures of 3 and 4 were elucidated using HRMS and 1D and 2D NMR spectroscopic data. The structure of 4 was also confirmed by single crystal X-ray crystallographic analysis of its bis-4-O-p-nitrobenzoate (8). Formation of withaferin A homodimer (4) as the major product suggests regio- and stereoselectivity of the Diels-Alder [4 + 2] cycloaddition reaction of 9. Acetylation of 2-4 afforded their acetyl derivatives 5-7, respectively. Compounds 2-4 and 6-8 were evaluated for their cytotoxic activities against four prostate cancer (PC) cell lines (LNCaP, 22Rv1, DU-145, and PC-3) and normal human foreskin fibroblast (HFF) cells. Significantly, 4 exhibited improved activity compared to the other compounds for most of the tested cell lines.