4-substituted Phenyl Research Articles

Activity-Based Dicyanoisophorone Derivatives: Fluorogenic Toolbox Enables Direct Visualization and Monitoring of Esterase Activity in Tumor Models.

The visualization and spatiotemporal monitoring of endogenous esterase activity are crucial for clinical diagnostics and treatment of liver diseases. Our research adopts a novel substrate hydrolysis-enzymatic activity (SHEA) approach using dicyanoisophorone-based fluorogenic ester substrates DCIP-R (R = R1-R6) to evaluate esterase preferences on diverse substrate libraries. Esterase-mediated hydrolysis yielded fluorescent DCIP-OH with a nanomolar detection limit in vitro. These probes effectively monitor ester hydrolysis kinetics with a turnover number of 4.73 s-1 and catalytic efficiency (kcat/Km) of 106 M-1 s-1 (DCIP-R1). Comparative studies utilizing two-photon imaging have indicated that substrates containing alkyl groups (DCIP-R1) as recognition elements exhibit enhanced enzymatic cleavage compared to those containing phenyl substitution on alkyl chains (DCIP-R4). Time-dependent variations in endogenous esterase levels were tracked in healthy and liver tumor models, especially in diethylnitrosamine (DEN)-induced tumors and HepG2-transplanted liver tumors. Overall, fluorescence signal quantifications demonstrated the excellent proficiency of DCIP-R1 in detecting esterase activity both in vitro and in vivo, showing promising potential for biomedical applications.

Development of a selective COX-2 inhibitor: from synthesis to enhanced efficacy via nano-formulation.

Non-steroidal anti-inflammatory drugs NSAIDs are widely used for managing various conditions including pain, inflammation, arthritis and many musculoskeletal disorders. NSAIDs exert their biological effects by inhibiting the cyclooxygenase (COX) enzyme, which has two main isoforms COX-1 and COX-2. The COX-2 isoform is believed to be directly related to inflammation. Based on structure-activity relationship (SAR) studies of known selective COX-2 inhibitors, our aim is to design and synthesize a novel series of 2-benzamido-N-(4-substituted phenyl)thiophene-3-carboxamide derivatives. These derivatives are intended to be selective COX-2 inhibitors through structural modification of diclofenac and celecoxib. The compound 2-benzamido-5-ethyl-N-(4-fluorophenyl)thiophene-3-carboxamide VIIa demonstrated selective COX-2 inhibition with an IC50 value of 0.29 μM and a selectivity index 67.24. This is compared to celecoxib, which has an IC50 value of 0.42 μM and a selectivity index 33.8. Molecular docking studies for compound VIIa displayed high binding affinity toward COX-2. Additionally, the suppression of protein denaturation with respect to albumin was performed as an indicative measure of the potential anti-inflammatory efficacy of the novel compounds. Compound VIIa showed potent anti-inflammatory activity with 93% inhibition and an IC50 value 0.54 μM. In comparison, celecoxib achieved 94% inhibition with an IC50 value 0.89 μM. Although molecule VIIa demonstrated significant in vitro anti-inflammatory activity, adhered to Lipinski's "five rules" (RO5) and exhibited promising drug-like properties, it showed indications of poor in vivo activity. This limitation is likely due to poor aqueous solubility, which impacts its bioavailability. This issue could be addressed by incorporating the drug in niosomal nanocarrier. Niosomes were prepared using the thin-film hydration technique. These niosomes exhibited a particle size of less than 200 nm, high entrapment efficiency, and an appropriate drug loading percentage. Transmission electron microscopy (TEM) and differential scanning calorimetry (DSC) studies revealed that the niosomes were spherical and demonstrated compatibility of all of its components. The drug release study indicated that the pure drug had limited practicality for in vivo use. However, incorporating the drug into niosomes significantly improved its release profile, making it more suitable for practical use.

Quercetin analogues of kojic acid as strong antioxidant derivatives: Theoretical insights

Kojic acid is a natural product produced by many fungal species and has a wide range of applications. The chelating and antioxidant capacity are associated with their chemical and biological properties. In this study, some molecular modifications were proposed and substituted and hydroxylated phenyl moieties were introduced in the basic structure of kojic acid. The antioxidant capacities were calculated by DFT/B3LYP/6-311++G(2d,2p). Different antioxidant mechanisms were considered such as frontier molecular orbitals (HOMO, LUMO, and GAP), electron (IP, SET, and SPLET), or hydrogen transfers (BDEOH and HAT) on gas phase and PCM methods. The phenyl increases the antioxidant capacity, especially when an electron donating group (EDG) is found at the para position of the phenyl ring when compared to electron withdrawing groups (EWGs), for all studied mechanisms. The chemical stability agrees with spin density contributions for their cationic free radicals and semiquinones. A structural similarity between hydroxylated derivatives of kojic acid and quercetin was observed on gas phase and water. The lower BDEOH values ​​at the phenol positions are more important for the antioxidant capacity than at the enol position. Phenolic semiquinones are more stables than enolic ones. The chemical stability depends on the number of resonance structures and the positions where the unpaired electron can be found with the highest contributions. In conclusion, phenyl substitution is a valuable molecular modification for the increase on antioxidant capacity of kojic acid. Quercetin analogues of kojic acid were proposed as strong antioxidant derivatives.

Theoretical Investigation on Carbazole Derivatives as Charge Carriers for Perovskite Solar Cell

The study explores carbazole‐based organic molecules as transport layers in durable perovskite solar cells, focusing on their optoelectronic and charge transfer properties. Thirteen carbazole derivatives are systematically analyzed via density functional theory (DFT) calculations to understand their structure and optoelectronic characteristics. Substituents like bromo, phenyl, thiophenyl, and pyridyl at positions 3,6‐ and 2,7‐ of carbazole were studied. Phenyl and thiophenyl substitutions lowered highest occupied molecular orbital (HOMO) energy levels, while bromo and pyridyl increased them, tuning HOMO energies from −5.45 to −6.03 eV. These energies align well with perovskite materials valence bands, with absorbance primarily below 400 nm, complementing perovskite absorption. The compounds showed high light‐harvesting efficiencies (LHEs) (0.22 to 0.94) and improved radiative lifetimes. Theoretical investigations identified most compounds as effective p‐type hole‐transport materials (HTM), except 3,6‐ and 2,7‐dithiophenyl carbazoles, which exhibited n‐type behavior due to low hole reorganization energies. Overall, the study highlights computational design's role in developing carbazole derivatives as promising charge carrier precursors for perovskite solar cells.

Cycloadditions of 4-Alkenyl-2-aminothiazoles with Nitroalkenes in the Formal Synthesis of Pramipexole: An Experimental and Computational Study.

4-Alkenyl-2-dialkylaminothiazoles act as in-out dienes in [4 + 2] cycloaddition reactions with nitroalkenes, furnishing 2-amino-6-nitro-4,5,6,7-tetrahydrobenzothiazoles in moderate to good yields, accompanied by a subsequent 1,3-H migration. These transformations proceed with exquisite site-, regio-, and diastereoselectivity. This strategy is further enriched by revealing a novel route for pramipexole synthesis. The examination of the potential energy surfaces associated with the four possible reaction pathways for the Diels-Alder cycloaddition (relative approach of the diene-dienophile and endo/exo approach of the nitro group) not only aligns with experimental observations but also unveils key mechanistic insights. Specifically, computational analyses uncover the favored pathway yielding 6-nitro-4,5,6,7-tetrahydrobenzothiazoles, with some instances proceeding through a two-step mechanism involving a tandem sequence of chemical processes, and the influence of various factors such as dienophile structure and the approach mode of the nitro group. Additionally, the stabilization of the exo-transition states, particularly facilitated by phenyl substitution in the dienophile, is highlighted. Asynchronicity, dipole moment, and other parameters indicative of polar character further characterize these Diels-Alder reactions. Conceptual DFT calculations underscore the pivotal role of the 1,3-thiazole ring in enhancing dienic activation and dictating regioselectivity, emphasizing interactions between the C5 of the thiazole nucleus and the Cβ atom of the nitroalkenes.

N-(1H-Benzo[d]imidazol-2-yl)-1-(3-substituted phenyl) methanimines as optoelectronic and nonlinear optical materials: spectroscopic and computational approaches

N-(1H-Benzo[d]imidazol-2-yl)-1-(3-substituted phenyl) methanimines as optoelectronic and nonlinear optical materials: spectroscopic and computational approaches

Evaluation of Novel Diaza Cage Compounds as MRP Modulators in Cancer Cells.

Novel MRP modulators are needed to combat MRP-mediated multidrug resistance (MDR) in cancer cells. Anticancer drug resistance is the main problem in cancer therapy. Causative multidrug efflux pumps are attractive target structures for the development of inhibitors of their activity. We synthesized novel cage dimeric 1,4-dihydropyridines to evaluate them as MRP modulators in cancer cells targeting MRP1, MRP2, and MRP4. Cage compounds were synthesized by solution dimerization of monomeric 1,4-dihydropyridines and a final functionalization reaction. The MRP modulation was determined in cellular efflux assays by the use of the flow cytometry technique as well as cellular fluorescent measurements with each fluorescent substrate of the efflux pumps. Difluoro phenyl and methoxy or dimethoxy benzyl substitutions were most favourable for the MRP1 and MRP2 inhibition, whereas monofluor phenyl and dimethoxy benzyl substitutions were most favourable for the MRP4 inhibition. Effective inhibitors were identified that were demonstrated to restore the respective cancer cell line sensitivity for the anticancer drug as a proof-of-concept that encourages further preclinical studies.</p>.

Photochemical Generation and Characterization of C-Aminophenyl-Nitrilimines: Insights on Their Bond-Shift Isomers by Matrix-Isolation IR Spectroscopy and Density Functional Theory Calculations.

The intriguing ability of C-phenyl-nitrilimine to co-exist as allenic and propargylic bond-shift isomers motivated us to investigate how substituents in the phenyl ring influence this behavior. Building on our previous work on the meta- and para-OH substitution, here we extended this investigation to explore the effect of the NH2 substitution. For this purpose, C-(4-aminophenyl)- and C-(3-aminophenyl)-nitrilimines were photogenerated in an argon matrix at 15 K by narrowband UV-light irradiation (λ = 230 nm) of 5-(4-aminophenyl)- and 5-(3-aminophenyl)-tetrazole, respectively. The produced nitrilimines were further photoisomerized to carbodiimides via 1H-diazirines by irradiations at longer wavelengths (λ = 380 or 330 nm). Combining IR spectroscopic measurements and DFT calculations, it was found that the para-NH2-substituted nitrilimine exists as a single isomeric structure with a predominant allenic character. In contrast, the meta-NH2-substituted nitrilimine co-exists as two bond-shift isomers characterized by propargylic and allenic structures. To gain further understanding of the effects of phenyl substitution on the bond-shift isomerism of the nitrilimine fragment, we compared geometric and charge distribution data derived from theoretical calculations performed for C-phenyl-nitrilimine with those performed for the derivatives resulting from NH2 (electron-donating group) and NO2 (electron-withdrawing group) phenyl substitutions.

Mesophase Behavior of Molecules Containing Three Benzene Rings Connected via Imines and Ester Linkages.

Ten new compounds based on the methineazo-azomethine (CH=N-N=CH) and ester linking groups were prepared and investigated for their mesophase behavior and optical stability, and liquid crystals of 4-substituted phenyl methineazo-azomethine phenyl 4-alkoxybenzoates, I n a-e , were investigated. An alkoxy group with a length between 8 and 12 carbons is attached to the phenyl eater wing, while the other terminal ring is substituted in its 4-position with one of the polar NO2, F, Cl, CH3O, and N(CH3)2 groups. The molecular structures of the newly prepared compounds were verified by using 1H NMR, 13C NMR, and elemental analysis. Differential scanning calorimetry and polarized optical microscopy were applied to investigate their mesophase behavior. All members of the prepared homologous series showed excellent thermal mesomorphic stability over wide temperature ranges. The geometrical and thermal properties of the investigated compounds were verified via density functional theory (DFT). The theoretical results revealed that all of the compounds are almost planar. Finally, the experimentally established values of the mesophase data were correlated with the predicted quantum chemical characteristics evaluated by DFT.

Drug Design, In Silico-Profiling of New Pyrrole Derivatives: Promising Anticancer Agents Against Acute Myeloid Leukemia

Molecular docking simulation and synthesis of five compounds of N2, N4-bis (2-(4-substituted phenyl)-4-oxothiazolidin-3-yl)-3,5-dimethyl-1H-pyrrole-2,4-dicarboxamide was carried out to evaluate their theoretical binding affinities, targeting acute myeloid leukemia (AML). The chemical structure of the molecules was accurately drawn using ChemDraw Professional 19.1 software. The designed compounds were evaluated for their selectivity towards FLT3's ATP pocket (PDB ID:6JQR) in comparison with the reference ligand (Gilteritinib) by using GOLD suite from the Cambridge Crystallographic Data Centre (CCDC) software (Version 2021.2.0). All the designed compounds exhibited good binding energies with the receptor active pocket and had promising activity. Compounds 2E and 3E showed the highest PLP Fitness (83.30, 80.86 respectively) and it is higher than that of Gilteritinib (71.91). In-silico ADME and drug-likeness studies were performed by using the Swiss ADME server. The results showed that most of the designed compounds expected to be absorbed from the GIT. Compounds 2B-E have high expected GI absorption. All the investigated compounds have no predicted BBB penetration. Additionally, compounds 2A, 2C, 2D, and 3A are not a substrate to P-gps which may indicate a lower expected incidence of resistance by cancer cells in vitro studies. Finally, all of the investigated compounds are not considered to inhibit CYP1A2 enzyme, except for compounds 2A and 3D.

Quantitative structure-activity relationship of 2,6-dimethoxy-N-(3-(4-substituted phenyl)isoxazol-5-yl)benzamide for the inhibition of chitin synthesis.

Previously, we found that 5-(2,6-dimethoxybenzoylamino)-3-phenylisoxazoles (IOXs) inhibit chitin synthesis in the cultured integument of Chilo suppressalis. In this study, IOXs with various substituents at the para-position of the 3-phenyl ring were synthesized, and the concentrations required to inhibit chitin synthesis to 50% (IC50) were determined for all compounds. The introduction of halogens-such as F, Cl, and Br-and small alkyls-such as Me, Et, Pr, and n-Bu-at the 3-phenyl ring slightly enhanced the activity. However, the activity decreased drastically with the introduction of NO2, CF3, and t-Bu. The quantitative analysis of the substituent effect at the 3-phenyl ring on chitin-synthesis inhibition using the Hansch-Fujita method showed that the hydrophobic substituent with the optimum value was favored for the activity, but the bulky substituent in terms of E s was detrimental to the activity.

Tailoring Emission Color Shifts in Mechanofluorochromic-Active AIE Systems of Carbazole-Based D-π-A Conjugates: Impact of π Spacer Unit Variants.

The expanding field of organic electronics has led to the emergence of donor-π-acceptor (D-π-A) systems as promising candidates for various optoelectronic applications. Recent advancements in the design of organic fluorophores allow precise modulation of their optical properties in the solution and solid states, broadening their utility. Here, we synthesize and characterize two series of D-π-A systems based on carbazole-cyanostilbene compounds (3a-c and 4a-c), which feature differences in π-spacer groups and substitution on the acceptor cyanostilbene units. These compounds exhibit intramolecular charge transfer (ICT) characteristics, with 3c possessing a phenyl spacer and -CF3 substitution displaying notable solvatochromism and polarity-enhanced emission (PEE). Additionally, both series show aggregation-induced emission (AIE), with emission color shifts controlled by spacer groups. These compounds demonstrate diverse emissive behaviors, including locally excited (LE), twisted intramolecular charge transfer (TICT), and π-π stacked aggregated states, contributing to the AIE phenomenon. Compounds with phenyl spacers (3a-c) exhibit higher solid-state quantum yields than those of thiophene (4a-c). Furthermore, the impact of spacer groups and acceptor substitutions on the solid-state emissive properties and mechanofluorochromism (MFC) are highlighted. Compounds with phenyl spacers and substitution (3a, 3c) show a blue-shifted MFC, while those with thiophene (4a, 4c) display a red-shifted MFC. These findings offer insights into the development of advanced materials with tunable emission properties and high thermal stability for optoelectronic applications.

In-silico Studies, Design, and Synthesis of Pyrimidine-linked Benzothiazoles for its Anticonvulsant Potential.

The objective of the study was to design and synthesize a series of N-(6-substituted-1,3-benzothiazole- 2-yl)-2-{[6-(3-substitutedphenyl)-5-cyano-2-sulfanylpyrimidine-4-yl)]amino}acetamide derivatives BPD (1-15) that contains key pharmacophores required for anticonvulsant action. The titled compounds (BPD 1-15) were synthesized by reacting 2-substituted-N-(6-chlorobenzo[d]thiazol2-yl)acetamide with 4-amino-6-(4-substituted phenyl)-2-mercapto pyrimidine 5-carbonitrile in the presence of potassium carbonate and dry acetone. The synthesized compounds BPD (1-15) were assessed in vivo by the maximum electric shock (MES) test and the subcutaneous pentylenetetrazol (scPTZ) test in mice. The neurotoxicity test was performed by the rotarod test. A molecular docking study of title compounds with a sodium channel receptor (PDB ID: 1BYY) was carried out using the SP Docking protocol of the Glide module of the Maestro. Pharmacophore modeling was used to qualitatively identify the chemical characteristics for ligand binding and their spatial configurations in the 3D space of the active site. Among the studied compounds, BPD-15 and BPD-5 compounds showed significant action in both the MES and scPTZ models, with no neurotoxicity. BPD-15 & BPD-5 were relatively safe in acute toxicity testing. Compounds BPD-15 and BPD-5 showed good dock scores of -6.434 and -6.191, respectively. Thus, the compounds BPD-15 and BPD-5 have shown a considerable affinity towards the sodium channel as compared to the standard drug Riluzole. Compound BPD-14 showed good drug compatibility, and compounds BPD-1, BPD-2, BPD-11, BPD-12, BPD-13, BPD-14, BPD-15 showed good ADME values.

Steric Control of Luminescence in Phenyl-Substituted Trityl Radicals.

Triphenylmethyl (trityl) radicals have shown potential for use in organic optoelectronic applications, but the design of practical trityl structures has been limited to donor/radical charge-transfer systems due to the poor luminescence of alternant symmetry hydrocarbons. Here, we circumvent the symmetry-forbidden transition of alternant hydrocarbons via excited-state symmetry breaking in a series of phenyl-substituted tris(2,4,6-trichlorophenyl)methyl (TTM) radicals. We show that 3-fold phenyl substitution enhances the emission of the TTM radical and that steric control modulates the optical properties in these systems. Simple ortho-methylphenyl substitution boosts the photoluminescence quantum efficiency from 1% (for TTM) to 65% at a peak wavelength of 612 nm (for 2-T3TTM) in solution. In the crystalline solid state, the neat 2-T3TTM radical shows a remarkably high photoluminescence quantum efficiency of 25% for emission peaking at 706 nm. This has implications in the design of aryl-substituted radical structures where the electronic coupling of the substituents influences variables such as emission, charge transfer, and spin interaction.

Synthesis and cytotoxicity of novel 6,8,9-trisubstituted purine analogs against liver cancer cells

A series of novel 6-(substituted phenyl piperazine)-8-(4-substituted phenyl)-9-cyclopentyl purines, 10–51, were synthesized by a four-step synthesis, achieving an overall yield of about 43 %. The reaction conditions were effectively optimized, and the final products were obtained with high purity and yield in all synthesis steps. The synthesized nucleobases were evaluated for their in vitro cytotoxic activities on selected human cancer cell lines (HUH7 (liver), HCT116 (colon), and MCF7 (breast)) using the Sulforhodamine B (SRB) assay. Among these analogs, compounds bearing 4-trifluoromethyl phenyl (19, 20 and 21), 4-methoxy phenyl (27) and 4-fluoro phenyl (34) substitutions at C-8 of purine were the most potent, and they were also analyzed in drug-resistance and drug-sensitive hepatocellular cancer cell (HCC) panels. Compound 19 displayed remarkable anticancer activities (IC50 = 2.9–9.3 μM) against Huh7, FOCUS, SNU475, SNU182, HepG2, and Hep3B cells compared to the positive control, Fludarabine. Additionally, the pharmacological properties and toxicity profiles of the molecules were investigated computationally by the Swiss-ADME and Pro-Tox II online tools, respectively. Results showed that our compounds have favorable physicochemical characteristics for oral bioavailability and do not reveal any toxicity endpoints such as carcinogenicity, immunotoxicity, mutagenicity, or cytotoxicity.

Crystal structure, spectral characterization, in vitro, molecular docking and DFT studies of pyranopyrazole derivatives

Two Pyranopyrazole derivatives, namely, methyl-11-(2-chlorophenyl)-16-methyl-8-[(4-methylbenzene)sulfonyl], -14-phenyl-12-oxa-8,14,15-triazatetracyclo[8.7.0.02,7.013,17] heptadeca-2(7), 3, 5, 13(17), 15-pentaene-10-carboxylate, C38H37N3S1O5 and butyl‑16-methyl-8-[(4-methylbenzene)sulfonyl]-11,14-diphenyl-12-oxa-8,14,15-triazatetracyclo[8.7.0.02,7.013,17] heptadeca-2(7),3,5, 13(17), 15-pentaene-10-carboxylate, C35 H30 Cl N3 O5 S with phenyl and chlorophenyl substitutions were synthesized successfully, and crystallized by the slow evaporation technique. The pyranopyrazole derivatives were characterized by spectroscopic techniques including UV–visible, FTIR, and mass spectroscopy, and their 3D-structural arrangements were also confirmed by single crystal XRD studies. Both compounds crystallize in the triclinic crystal system with the centrosymmetric space group P-1, which is identified by the X-ray single-crystal structure. These compounds were examined for in vitro and molecular docking studies with the enzymes 1hny, 1pgg, and 4 cox and thus correspond to diabetes and inflammation. The observed results showed better binding energy and inhibition constants for inflammation involving enzymes. The chemical reactivity and electronic arrangement of the compounds have been revealed by DFT studies.

Spectroscopic study on enantiomeric Ni(II) complexes of porphyrin-porphyrin Tröger's base and porphyrin-chlorin spiro-Tröger's base derivatives supported by DFT calculations

The chiral properties of nickel(II) complexes of porphyrin-porphyrin Tröger's base and porphyrin-chlorin spiro-Tröger's base with phenyl or 3-methoxyphenyl substitutions in their meso-positions were studied. Enantioseparation of racemic mixtures was investigated via high-performance liquid chromatography (HPLC) on an analytical ReproSil Chiral-NR column. The optimal conditions were utilized for a multimilligram scale isolation with a semipreparative column. The purity of the isolated enantiomers was determined by HPLC and UV–Vis spectroscopy. The absolute configurations of the isolated enantiomers were determined by evaluating the Cotton effect in electronic circular dichroism spectra. The determination was supported by TDDFT calculations, in which good agreement was achieved between the experimental and simulated spectra. The maximum molar ellipticity values, [θ]λmax given in deg ∙ cm2 ∙ dmol−1, were [θ]435 = 1.73 ∙ 107 for phenyl spiroTB and [θ]436 = 1.24 ∙ 107 and [θ]436 = 2.15 ∙ 107 for 3-methoxyphenyl TB and spiroTB, respectively.

Stereochemical optimization of N,2-substituted cycloalkylamines as norepinephrine reuptake inhibitors.

The norepinephrine transporter (NET), encoded by the SLC6A2 gene, is one of three key monoamine neurotransmitter transporters. Inhibition of NET-mediated reuptake of norepinephrine by monoamine reuptake inhibitors has been the main therapeutic strategy to treat disorders such as depression, ADHD and Parkinson's disease. Nevertheless, lack of efficacy as well as risk of adverse effects are still common for these treatments underscoring the necessity to improve drug discovery efforts for this target. In this study, we developed new inhibitors based on 4-((2-(3,4-dichlorophenyl)cyclopentyl)amino)butan-1-ol (8), a potent NET inhibitor, which emerged from earlier virtual screening efforts using a predictive proteochemometric model. Hence, we optimized the N,2-substituted cycloalkylamine scaffold in three regions to design twenty new derivatives. To establish structure-activity relationships for these NET inhibitors, all novel compounds were tested utilizing an impedance-based 'transporter activity through receptor activation' assay. Moreover, all stereoisomers of the most potent compound (27) were synthesized and evaluated for their inhibitory potencies. Initial screening indicated that modifications in the cyclopentylamine moiety and phenyl substitutions decreased NET inhibition compared to 8, emphasizing the importance of the five-membered ring, secondary amine and dichloro-substitution pattern in NET binding. Substituting the original butylalcohol at the R 2 position with a rigid cyclohexanol yielded lead compound 27, with potency similar to reference inhibitor nisoxetine. Pharmacological characterization of all eight stereoisomers of 27 revealed varying inhibitory potencies, favoring a trans-orientation of the N,2-substituted cyclopentyl moiety. Molecular docking highlighted key interactions and the impact of a hydrophilic region in the binding pocket. This study presents a novel set of moderate to highly potent NET inhibitors, elucidating the influence of molecular orientation in the NET binding pocket and offering valuable insights into drug discovery efforts for monoamine transport-related treatments.

Discovery of (2-(4-Substituted phenyl)quinolin-4-yl)(4-isopropylpiperazin-1-yl)methanone Derivatives as Potent Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors.

Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an increasingly important role in the treatment of hyperlipidemia. In pursuit of potent small molecules that block the PCSK9/low-density lipoprotein receptor (LDLR) protein-protein interaction (PPI), a series of 2-phenylquinoline-4-carboxylic acid derivatives were designed and synthesized based on previously derived molecules. In the in vitro PPI inhibition test, compounds M1, M12, M14, M18 and M27 exhibited potent activities with IC50 values of 6.25 μM, 0.91 μM, 2.81 μM, 4.26 μM and 0.76 μM, respectively, compared with SBC-115337 (IC50 value of 9.24 μM). Molecular docking and molecular dynamics simulations revealed the importance of hydrophobic interactions in the binding of inhibitors to the PPI interface of PCSK9. In LDLR expression and LDL uptake assays, the tested compounds M1, M12 and M14 were found to restore LDLR expression levels and to increase the extracellular LDL uptake capacity of HepG2 cells in the presence of exogenous PCSK9. Collectively, novel small-molecule PCSK9/LDLR PPI inhibitors (especially M12) with in vitro lipid lowering ability, were discovered as lead compounds for further development of hypolipidemic drugs.

Synthesis and investigation of antibacterial activity of 1-(4-substituted phenyl)-5-oxopyrrolidine-3-carbohydrazide derivatives

&#x0D; &#x0D; &#x0D; &#x0D; Hydrazides are very important precursors for the synthesis of a wide variety of derivatives, including heterocyclic compounds of biological interest in drug design and discovery. Acid hydrazides with a pyrrole, thiophene, furan, quinoline, isoquinoline, isoxazole and benzimidazole core in the structure were found to be used in medicine, pharmacy, agriculture and many other fields.&#x0D; In the search for compounds with antibacterial properties, mono- and dihydrazides were used in this study to prepare 1-(4-substituted phenyl)-5-oxopyr-rolidine-3-carbohydrazide derivatives bearing the corresponding hydrazone and azole substituents.&#x0D; The formation of the target compounds was performed via condensation reactions with the chosen aromatic aldehydes and isatin, which led to the construction of the appropriate hydrazone-type structures as well as with diketones which afforded compounds with pyrazole and pyrrole nuclei.&#x0D; In addition, a preliminary antibacterial evaluation of the synthesised compounds was performed using the gram-positive Bacillus subtilis and the gramnegative Escherichia coli bacterial strains. As it was expected, the evaluation revealed potential antibacterial candidates that can help address the global challenges of antibiotic resistance and infectious disease outbreaks.&#x0D; &#x0D; &#x0D; &#x0D;