Derivatives 3a Research Articles

Employing acetoacetamide as a key synthon for synthesizing novel thiophene derivatives and assessing their potential as antioxidants and antimicrobial agents

AbstractThe objective of this study is to synthesize novel heterocyclic scaffolds containing a thiophene moiety using easily accessible acetoacetamide as a key synthon. The reaction of acetoacetamide with diazonium salts resulted in the formation of the corresponding thiophene derivatives 4a–c. Additionally, the reaction of acetoacetamide derivative 3 with malononitrile, ethyl cyanoacetate, or 2‐cyanoacetamide, along with elemental sulfur, under refluxing in dioxane containing triethylamine afforded thiophene‐containing derivatives 5a–c. Furthermore, compound 3 reacted with phenyl isothiocyanate in dry dimethylformamide and K2CO3 to yield compound 7. In situ alkylation of the non‐isolable salt 6 was achieved by the addition of methyl iodide, resulting in the formation of methylthio‐thiophene‐2‐carboxamide 8. Compound 7 was employed with numerous alpha‐halogenated reagents in ethanol, affording thiazole derivative 9 and thiophene derivatives 10a and 10b, respectively. Moreover, compound 8 was reacted with hydrazine to produce the 1H‐pyrazole‐4‐carboxamide derivative 11. Additionally, refluxing acetoacetamide derivative 3 with malononitrile and/or ethyl cyanoacetate in dioxane, in the presence of catalytic amount of triethylamine afforded 4‐imino‐3,7‐dimethyl‐4H‐pyrido[1,2‐a]thieno[3,2‐e]pyrimidin‐9(5H)‐one derivatives 12a and 12b. Furthermore, the reactivity of acetoacetamide derivative 3 with 2‐cyanoacetohydrazide was investigated through refluxing the reactants in dioxane, which subsequently yielded the corresponding cyanoacetamide derivative 13. The chemical identity of the newly synthesized compounds was determined by employing infrared spectroscopy (IR), 1H NMR, and 13C NMR techniques. Newly synthesized heterocycles incorporating thiophenes were evaluated for their antioxidant and antimicrobial potentials. Notably, thiophene scaffolds 5a, 10b, 11, and 13 displayed notable antioxidant and antimicrobial activities.

Ultrasound-assisted synthesis of novel Schiff bases from 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde and their cytotoxicity, apoptosis, cell cycle, molecular docking, and ADMET profiling

With the ultimate goal of discovering new anticancer agents, this study involved the design and synthesis of fifteen novel Schiff bases 4a,b, 5, 6a–d, 7a–e, and 8–10 which contain 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole moiety. The synthetic method depended on reaction of 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde (3) with a series of aromatic and heteroaryl amines under ultrasound irradiation to explore the influence of aromatic and heteroaryl rings on biological activity. The chemical structures of these Schiff bases were fully elucidated using various spectral and elemental analyses. The antiproliferative activities of the Schiff bases were studied by the standard SRB method. Among the new 15 Schiff bases, derivatives 4a,b, 5, and 7b have significant cytotoxic effects against PC3, HepG2, and HCT116 cancer cell lines. These four bioactive Schiff bases significantly increased the late apoptosis of all studied tumor cells. Also, both products 4a and 4b arrested the cell cycle at the G1 phase, while both compounds 5 and 7b arrested the S and G2 phases against PC3 cells. In addition, the products 4a, 4b, 5, and 7b have promising high abilities to arrest the cell cycle at the G2 phase against HepG2 and HCT116 cells. The different substitutions on the aryl ring were the basis for the structure–activity relationship study. The molecular docking study confirmed good binding interactions of these compounds with Cyclin-dependent kinase 8 (CDK-8) receptor, while the absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction supported that these bioactive products can be promising anticancer agents.

In-vitro and in-silico investigations of SLC-0111 hydrazinyl analogs as human carbonic anhydrase I, II, IX, and XII inhibitors.

Two novel series of hydrazinyl-based benzenesulfonamides 9a-j and 10a-j were designed and synthesized using SLC-0111 as the lead molecule. The newly synthesized compounds were evaluated for their inhibitory activity against four different human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. Both the series reported here were practically inactive against the off-target isozyme hCA I. Notably, derivative 10a exhibited superior potency (Ki of 10.2 nM) than acetazolamide (AAZ) against the cytosolic isoform hCA II. The hCA IX and XII isoforms implicated in tumor progression were effectively inhibited with Kis in the low nanomolar range of 20.5-176.6 nM and 6.0-127.5 nM, respectively. Compound 9g emerged as the most potent and selective hCA IX and XII inhibitor with Ki of 20.5 nM and SI of 200.1, and Ki of 6.0 nM and SI of 683.7, respectively, over hCA I. Furthermore, six compounds (9a, 9h, 10a, 10g, 10i, and 10j) exhibited significant inhibition toward hCA IX (Kis = 27.0, 41.1, 27.4, 25.9, 40.7, and 30.8 nM) relative to AAZ and SLC-0111 (Kis = 25.0 and 45.0 nM, respectively). These findings underscore the potential of these derivatives as potent and selective inhibitors of hCA IX and XII over the off-target hCA I and II.

Design, synthesis and anti-tumor evaluation of novel thiohydantoin congeners as androgen receptor antagonists with in vivo study

Novel thiohydantoin derivatives were designed as androgen antagonists based on the binding pattern of enzalutamide to the androgen receptor that avoided the bifurcated activation pattern of dihydrotestosterone. Twelve thiohydantoin derivatives were synthesized following Michael-type addition which were fully characterized. The dicyanide derivatives 3a showed the best LNCaP inhibition demonstrating IC50 of 2.64 µM with a potential to inhibit its S-phase reducing the natural DNA transactivation of androgens. Moreover, apoptosis initiation was observed in the early phase with 22.74 % in contrast to 9.06 % at the late phase with respect to 0.44 % and 0.13 % of the control cells at early and late stages, respectively. In vivo evaluation of 3a significantly ameliorated the testosterone-induced increase in the prostate index and weight as compared to finasteride. This was confirmed by the histopathological examinations of prostatic tissues that demonstrated a reduction in the accompanied histopathological changes as well as lowering the immunohistochemical up-regulation of androgen receptors induced by testosterone. Moreover, molecular docking simulation justified the achieved biological activity.

The activity of pyrazolo[4,3-e][1,2,4]triazine and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives in monolayer and spheroid breast cancer cell cultures

In the last decade, an increasing interest in compounds containing pyrazolo[4,3-e][1,2,4]triazine moiety is observed. Therefore, the aim of the research was to synthesise a novel sulphonyl pyrazolo[4,3-e][1,2,4]triazines (2a, 2b) and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives (3a, 3b) to assess their anticancer activity. The MTT assay showed that 2a, 2b, 3a, 3b have stronger cytotoxic activity than cisplatin in both breast cancer cells (MCF-7 and MDA-MB-231) and exhibited weaker effect on normal breast cells (MCF-10A). The obtained results showed that the most active compound 3b increased apoptosis via caspase 9, caspase 8, and caspase 3/7. It is worth to note that compound 3b suppressed NF-κB expression and promoted p53, Bax, and ROS which play important role in activation of apoptosis. Moreover, our results confirmed that compound 3b triggers autophagy through increased formation of autophagosomes, expression of beclin-1 and mTOR inhibition. Thus, our study defines a possible mechanism underlying 3b-induced anti-cancer activity against breast cancer cell lines.

Chemical constituents with antioxidant activity from the branches and leaves of Hultholia mimosoides

Four undescribed homoisoflavanoids (1–4), one homoflavonoid (5), ten dibenzoxocin derivatives (6a–10a and 6b–10b), one dibenzoxocin-derived phenolic compound (11), one diterpenoid (13), three aliphatic dicarboxylic acid derivatives (14–16), together with the known diterpenoid 12-O-ethylneocaesalpin B (12) were obtained from the branches and leaves of Hultholia mimosoides. Their structures were elucidated by extensive spectroscopic techniques. Notably, each of the dibenzoxocins 6−10 existed as a pair of interconvertible atropisomers and the conformation for these compounds was clarified by NMR and ECD analyses. Protosappanin F (11) was a previously undescribed dibenzoxocin-derived compound in which one of the benzene rings was hydrogenated to a polyoxygenated cyclohexane ring and an ether linkage was established between C-6 and C-12a. The isolated polyphenols were tested for induction of quinone reductase and compounds 3 and 8 showed potent QR-inducing activity in Hepa-1c1c7 cells.

An efficient synthesis and anticancer evaluation of 1,2,3-triazolo-indole-2-carboxylate derivatives

A new series of 1,2,3-Triazole bearing Indole derivatives (6a–j, 8a & 9a) was developed and examined for their preliminary anticancer effects against five human cancer cell lines such as breast cancer cell line (MCF-7), human lung cancer cell line (A549), human colon cancer cell line (Colo-205), human prostate cancer cell line (DU-145) and human breast cancer cell line (MDA MB-231). The well-known chemotherapeutic agent as etoposide used as a positive control. Among synthesized compounds, six compounds (6a, 6b, 6c, 6d, 6f and 8a) were possessed more potent anticancer activities than standard drug.

Synthesis of bioactive heterocyclic compounds using camphor

The aim of the work was to synthesize novel heterocyclic compounds derived from camphor with antibacterial activity. The pyridazine, xanthene, pyranothiazole, pyridinothiazole, thiophene and pyrazole derivatives were produced from 4,11,11-trimethyl-9-phenyl-7-(2-phenylhydrazono)-3,4,5,6,7,9-hexahydro-1H-1,4-methanoxanthen-8(2H)-one (1). Thiophene derivatives 6a,b were produced according to the Gewald’s reaction for  thiophene synthesis. On the other hand, pyranothiazol derivatives 8a,b were synthesized by the multicomponent reactions between xanthene derivative 5, benzaldehyde and ethylcyanoacetate or malononitrile in ethanol/triethylamine. Whereas, pyridinothiazole derivative 9 was produced in ethanol/ammonium acetate by the multicomponent reaction between xanthene derivative 5, benzaldehyde and malononitrile. The antibacterial activity of the synthesized compounds was evaluated against E. coli bacteria. All synthesized compounds showed moderate activity against E. coli bacteria.    KEY WORDS: Anti-microbial, Camphor, Heterocyclic, Pyrazol-3(2H)-one, Thiazol-4(5H)-one, Thieno[3,2-d]thiazole, Xanthenes Bull. Chem. Soc. Ethiop. 2024, 38(4), 1069-1076.                                                          DOI: https://dx.doi.org/10.4314/bcse.v38i4.20

Structure-Activity Relationship Studies on Highly Functionalized Pyrazole Hydrazones and Amides as Antiproliferative and Antioxidant Agents.

Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure-activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10-22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC50 values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N-acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure-activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives.

Green synthesis, density functional theory (DFT), molecular docking, molecular dynamics simulation and biological activity of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives as PLA2 and proteinase K inhibitors

In diseases like atherosclerosis, rheumatoid arthritis, and sepsis, phospholipase A2 (PLA2) and proteinase K play a role in inflammation by releasing arachidonic acid (AA). The crucial step in the inflammatory process is believed to be the release of prostaglandins after PLA2 mobilizes AA. Drugs obstructing the COX and LOX pathways in the arachidonic acid cascade, drugs that inhibit these enzymes can treat inflammatory processes. To combat against these inflammatory promoters,the authors herein report an effective method for the synthesis of a series of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives (4a–h) under the effect of TiO2 as a photocatalyst in ethanolic medium, and their effect against phospholipase A2, as well as proteinase K, was evaluated. The results confirmed that using TiO2 (20 mg) as a photocatalyst exhibits excellent performance in terms of yield and reaction time. The yield of all the synthesized compounds is between 79 and 91 % in just 60 min. After closely evaluating the SAR of the examined compounds against both enzymes, it was discovered that compounds (4b, 4f) with electron-donating substituents have higher PLA2 inhibitory (%) activity than those with electron-removing substituents (4a, 4e). Compounds (4c, 4d) containing heterocyclic rings showed significantly higher proteinase inhibitory (%) activity when compared to other electron-donating or withdrawing compounds. It was further confirmed that studied compounds against both enzymes exhibited dose-dependent behavior. We studied the intermolecular interactions of the compounds by molecular docking with human non-pancreatic secretory phospholipase A2 and proteinase K. We evaluated the dynamical stability of the docked complexes using a 100 ns molecular dynamics simulation, which revealed stable interactions based on root mean square deviation/fluctuation (RMSD/RMSF), radius of gyration, Gibbs free energy landscapes, and principal component analyses (PCA). Moreover, the ADME properties of the compounds align with Lipinski’s rule of five, suggesting their potential as viable candidates for the development of therapies against inflammatory diseases. All compounds tested inhibited PLA2 more than proteinase K. However, compounds 4b and 4f better inhibited phospholipase A2, whereas compounds 4c and 4d showed better activity against proteinase K.

New phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamides as dual inhibitors against α-glucosidase and PTP-1B for the treatment of type 2 diabetes.

This study describes the design, synthesis, and evaluation of a novel series of phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamide derivatives (7a-l) as dual inhibitors of α-glucosidase and protein tyrosine phosphatase 1-B (PTB-1B). The latter enzymes are two important targets in the treatment of type 2 diabetes. The in vitro obtained data demonstrated that all title compounds 7a-l were more potent than the standard inhibitor acarbose against α-glucosidase while only four derivatives (7a, 7g, 7h, and 7h) were more potent than the standard inhibitor suramin against PTP-1B. Furthermore, these data showed that the most potent α-glucosidase inhibitor was compound 7i, with sixfold higher inhibitory activity than acarbose, and the most potent PTP-1B inhibitor was compound 7a with 3.5-fold higher inhibitory activity than suramin. Kinetic studies of compounds 7i and 7a revealed that they inhibited their target enzymes in a competitive mode. The docking study demonstrated that compounds 7i and 7a well occupied the active site pockets of α-glucosidase and PTP-1B, respectively. In silico pharmacokinetic and toxicity assays of the most potent compounds were performed, and the obtained results were compared with those of the standard inhibitors.

Nitrophenylpiperazine derivatives as novel tyrosinase inhibitors: design, synthesis, and in silico evaluations

A novel series of 4-nitrophenylpiperazine derivatives (4a–m) was designed and synthesized as potential tyrosinase inhibitors. Comprehensive characterization using 1H-NMR, 13C-NMR, CNH, and IR techniques was performed for all target compounds. Subsequently, the derivatives were evaluated for their inhibitory activity against tyrosinase. Among them, compound 4l, featuring an indole moiety at the N−1 position of the piperazine ring, exhibited a significant tyrosinase inhibitory effect with an IC50 value of 72.55 μM. Enzyme kinetics analysis revealed that 4l displayed mixed inhibition of the tyrosinase enzymatic reaction. Molecular docking was carried out in the enzyme’s active site to further investigate the enzyme-inhibitor interactions. Based on the findings, compound 4l shows promise as a lead structure for the design of potent tyrosinase inhibitors. This study paves the way for the development of more effective tyrosinase inhibitors for potential applications in various fields.

Experimental and theoretical investigation of 1,3-bis(3-hydroxypyridinium)propane dibromide dihydrate, tetrabromozincate hydrate, and tetrabromocuprate

Three gemini hydroxypyridine salts: 1,3-bis(3-hydroxypyridinium)propane dibromide dihydrate (1), 1,3-bis(3-hydroxypyridinium)propane tetrabromozincate hydrate (2), and 1,3-bis(3-hydroxypyridinium)propane tetrabromocuprate (3) were synthesized and characterized by X-ray diffraction, FTIR, Raman, NMR, and DFT methods. The dibromide salt (1) crystallizes with two water molecules. One of the two bromide anions is connected to the hydroxyl group of one pyridinium cation moiety through the O(10)-H(10)···Br(2)− hydrogen bond of 3.146(2) Å, while the other bromide anion, Br(1)− is surrounded by three water molecules. In 1,3-bis(3-hydroxypyridinium)propane tetrabromozincate (2) the water molecule acts as a bridge between the hydroxypyridinium cation and the tetrabromozincate anion, while the tetrabromocuprate anion interacts directly with the hydroxypyridinium cation. The molecular structures of the studied 1,3-bis(3-hydroxypyridinium)propane derivatives 1a, 2a, and 3a were optimized using the APF-D/6–311++G(d,p) method. The optimized structure of salt 1a resembles the crystal structure, while in salts 2a and 3a the structure of 1,3-bis(3-hydroxypyridinium)propane dication is bent to the U-form and the tetrabromomethallate anion is located in a niche. The significant role of the intermolecular interactions and hydrogen bonds was revealed based on IR spectra. The interpretation of 1H and 13C NMR spectra in DMSO-d6 was based on 2D experiments. The quantum theory of atoms in molecules (QTAIM) was employed to classify the strength of hydrogen bonds in salts 1, 2, and 3. Based on the σ-hole concept, intermolecular interactions in 2 and 3 were described.

Synthesis, Characterization, and Electrochemical Study of Novel Porphyrin Derivatives as Corrosion Inhibitors for Carbon Steel in HCl Solutions

This study involves the synthesis of some porphyrins derivatives, these are termed as 4,4',4'',4'''-(porphyrin-5,10,15,20-tetrayl)tetrakis(N-(6-aminoacridin-3-yl)benzamide) (3a), 4,4',4'',4'''-(porphyrin-5,10,15,20-tetrayl)tetrakis(N-(5-methoxybenzo[d]thiazol-2-yl)benzamide) (3b), 4,4'-(10,20-bis(3-hydroxyphenyl)porphyrin-5,15-diyl)bis(N-(6-aminoacridin-3yl)benzamide) (5a), and 4,4'-(10,20-bis(3-hydroxyphenyl)porphyrin-5,15-diyl)bis(N-(benzo[d]thiazol-2-yl)benzamide) (5b). These derivatives were synthesized using open circuit potential (OCP) and potentiodynamic polarization (PDP) in 0.1 M HCl solution methods. These derivatives were characterized using nuclear magnetic resonance (1H- and 13C-NMR) spectroscopy, mass spectra (ESI), and micro elemental analysis (CHN). The activity of these synthesized materials was investigated as a corrosion inhibitor using carbon steel (CS) as a model for corroded materials. The obtained results showed that the synthesized porphyrins derivatives were effective corrosion inhibitors to 0.1 M HCl solution for CS. In the case of the derivative 3a, a maximum inhibition efficiency (IE%) was recorded and it was around 74%. The derivative 3b showed an IE% of around 68.11%, while the %IE of 5a and 5b were around 18.98% and 45.16%, respectively. The best IE% value that was recorded for the derivative 3a has the potential to be effective anticorrosive coatings for industrial applications and act as mixture inhibitor because their ΔEcorr values are less than 85 mV. On the CS surface following treatment with compound 3a, the inhibitor mechanism for acidic medium (HCl) was investigated.

Utility of sulfachloropyridazine in the synthesis of novel anticancer agents as antiangiogenic and apoptotic inducers

In a search for new anticancer agents with better activity and selectivity, the present work described the synthesis of several new series of sulfachloropyridazine hybrids with thiocarbamates 3a-e, thioureids 4a-h, 5a-e and 4-substituted sulfachloropyridazines 6a, b, 7a, b and 8. The synthesized compounds were screened in vitro against a panel of 60 cancer cell lines in one dose assay. The most potent derivatives 3a, 3c, 4c, 4d, 5e, 7a and 7b were tested for their antiangiogenic activity by measuring their ability to inhibit VEGFR-2. The most potent compounds in VEGFR-2 inhibitory assay were further evaluated for their ability to inhibit PDGFR. In addition, the ability of 4c compound to inhibit cell migration on HUVEC cells and cell cycle effect on UO-31 cells has been studied. The pro-apoptotic effect of compound 4c was studied by the evaluation of caspase-3, Bax and BCl-2. Alternatively, the IC50 of compounds 3a, 3c, 4c, 5e, 7a and 7b against certain human cancer cell lines were determined. Re-evaluation in combination with γ-radiation was carried out for compounds 4c, 5e and 7b to study the possible synergistic effect on cytotoxicity. Docking studies of the most active compounds were performed to give insights into the binding mode within VEGFR-2 active site

New thiazole derivatives: Synthesis, X-ray crystal structure, Hirshfeld surface analysis, and biological evaluations as potential antimicrobial and antitumor agents

Thiazole ring has a wide range of biological activities which is proven by its presence in more than eighteen FDA-approved drugs in addition to several compounds that are currently under clinical investigation. Substitution of the thiazole ring at positions 2,4, and 5 led to new derivatives with potent biological activities. Interestingly, the bromination of ethyl 2-cyano-2-(4-methyl-3-phenylthiazol-2(3H)-ylidene)acetate (1) in acetic acid afforded (Z)-ethyl 2-(5-bromo-4-(bromomethyl)-3-phenylthiazol-2(3H)-ylidene)-2-cyanoacetate (2) instead of the expected bromomethyl derivative 3. The reaction of thiazole derivative 2 with p-anisidine or aniline produced the corresponding thiazole derivatives 5a,b. The synthesized compounds were characterized based on their spectral and elemental data. Moreover, the structure of compound 2 was determined through X-ray crystallography. The molecular structure of 2 was crystallized in the orthorhombic, Pna21, a = 15.8144 (6) Å, b = 9.0238 (4) Å, c = 11.3296 (4) Å, V = 1616.80 (11) Å3, Z = 4. Analysis of the dnorm map and fingerprint plot for all possible intermolecular interactions in the crystal structure of thiazole 2 indicated the importance of the Br…O, O…H, and Br…H interactions in the molecular packing. The O1…H14A (2.548 Å), Br1…O1 (3.211 Å) and Br2…H7B (2.931 Å) interactions are the most short contacts. In addition, the percentages of the Br…O, O…H, and Br…H contacts are 2.3, 10.3 and 22.1%, respectively. The antimicrobial activity of thiazole derivative 5a was tested, and the results revealed that it is equipotent to both Ampicillin against Staphylococcus aureus and to Gentamycin against Salmonella SP. In comparison to Doxorubicin, thiazole 5a showed less antitumor activity against the hepatocellular carcinoma (HepG-2) and colon carcinoma (HCT-116) cell lines.

Photodecarboxylative ring annulation of α‐ and β‐functionalized phthaloyl‐GABA derivatives: bioactive pyrroloisoindolinones with high quantum efficiency

The triplet‐sensitized (by the solvent acetone) as well as the direct (λex = 300 ‐ 320 nm) photochemical decarboxylation of N‐phthaloylated γ‐aminobutyric acid (GABA) derivatives are versatile and high‐yielding routes to benzopyrrolizidines via intramolecular electron transfer initiated decarboxylation followed by radical coupling. The ß‐mono‐ and ß,ß´‐disubstituted N‐phthaloyl GABA derivatives 7a‐7g, respectively, were applied as substrates. Decarboxylative photocyclization yielded hydroxy benzopyrrolizidines 8a‐8g in high chemical yields and with moderate diastereoselectivities from the ß‐monosubstituted substrates. The analogous α‐substituted GABA derivatives 11a‐11c were also applied as potential substrates for memory of chirality effects. The reaction quantum yields of the photodecarboxylation reactions for the parent GABA derivative 13 and for the new substrates 7h and 11a were determined by the quantum yield determination system (QYDS) and showed a remarkable concentration dependency indicating aggregation at higher substrate concentrations. Inhibition studies on the atherogenic human serine hydrolase cholesterol esterase showed derivatives 8a and 8d to exhibit a hyperbolic mode of inhibition with moderate IC50 values of about 60‐80 µM.

Design, synthesis and bioactivity study on oxygen-heterocyclic-based pyran analogues as effective P-glycoprotein-mediated multidrug resistance in MCF-7/ADR cell

P-glycoprotein (P-gp) imparts multi-drug resistance (MDR) on the cancers cell and malignant tumor clinical therapeutics. We report a class of newly designed and synthesized oxygen-heterocyclic-based pyran analogues (4a–l) bearing different aryl/hetaryl-substituted at the 1-postion were synthesized, aiming to impede the P-gp function. These compounds (4a–l) have been tested against cancerous PC-3, SKOV-3, HeLa, and MCF-7/ADR cell lines as well as non-cancerous HFL-1 and WI-38 cell lines to determine their anti-proliferative potency.The findings demonstrated the superior potency of 4a–c with 4-F, 2-Cl, and 3-Cl derivatives and 4h,g with 4-NO2, 4-MeO derivatives against PC-3, SKOV-3, HeLa, and MCF-7/ADR cell lines.Compounds 4a–c were tested for P-gp inhibition and demonstrated significant vigour against MCF-7/ADR cells with IC50 = 5.0–10.7 μM. The Rho123 accumulation assay showed that compounds 4a–c adequately inhibited P-gp function, as predicted. Furthermore, 4a or 4b administration resulted in MCF-7/ADR cell accumulation in the S phase, while compound 4c induced apoptosis by causing cell cycle arrest at G2/M. The molecular docking was applied to understand the likely modes of action and guide us in the rational design of more potent analogs. The investigate derivatives showed their good binding potential for p-gp active site with excellent docking scores and interactions. Finally, the majority of investigated derivatives 4a–c derivatives showed high oral bioavailability, but they did not cross the blood–brain barrier. These results suggest that they have favorable pharmacokinetic properties. Therefore, these compounds could serve as leads for designing more potent and stable drugs in the future.

7-O-tyrosyl Silybin Derivatives as a Novel Set of Anti-Prostate Cancer Compounds.

Silybin is a natural compound extensively studied for its hepatoprotective, neuroprotective and anticancer properties. Envisioning the enhancement of silybin potential by suitable modifications in its chemical structure, here, a series of new 7-O-alkyl silybins derivatives were synthesized by the Mitsunobu reaction starting from the silybins and tyrosol-based phenols, such as tyrosol (TYR, 3), 3-methoxytyrosol (MTYR, 4), and 3-hydroxytyrosol (HTYR, 5). This research sought to explore the antioxidant and anticancer properties of eighteen new derivatives and their mechanisms. In particular, the antioxidant properties of new derivatives outlined by the DPPH assay showed a very pronounced activity depending on the tyrosyl moiety (HTYR > MTYR >> TYR). A significant contribution of the HTYR moiety was observed for silybins and 2,3-dehydro-silybin-based derivatives. According to the very potent antioxidant activity, 2,3-dehydro-silybin derivatives 15ab, 15a, and 15b exerted the most potent anticancer activity in human prostate cancer PC-3 cells. Furthermore, flow cytometric analysis for cell cycle and apoptosis revealed that 15ab, 15a, and 15b induce strong G1 phase arrest and increase late apoptotic population in PC-3 cells. Additionally, Western blotting for apoptotic marker cleaved caspase-3 confirmed apoptosis induction by these silybin derivatives in PC-3 cells. These findings hold significant importance in the investigation of anticancer properties of silybin derivatives and strongly encourage swift investigation in pre-clinical models and clinical trials.

Synthesis, Identification and Preliminary Pharmacological Evaluation of New Hydrazone and 1, 3, 4-oxadiazole Derivatives of Ketorolac

New series of hydrazones (3a–b) and 1, 3, 4-oxadiazole S-alkylated derivatives (5a–b) of ketorolac (NSAID) were synthesized and their structures were identified by using ATR-FT-IR and ¹HNMR spectroscopic analytical techniques. The synthesized compounds were evaluated in vitro for their antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus), Gram-negative bacteria (Escherichia coli), and fungal species (Candida albicans). After the approval of the ethical committee in the college of pharmacy, University of Baghdad, In vivo screening for their anti-inflammatory activity was done using albino rats as an animal model that were subjected to white egg-induced acute inflammation. Results have shown that the target compounds were successfully synthesized, and it was discovered that they have mild to moderate activity against E.Coil and S.aureus while no effect has shown on C.albicans. In vivo studies showed they were effective in lowering paw edema thickness and had an anti-inflammatory effect similar to that of the standard (ketorolac)