Derivatives 2b Research Articles

Partial syntheses of aromatic amides: their anti-urease potential and docking studies

The aromatic amide: N-p-trans-coumaroyltyramine (1) was isolated for the first time from the stem bark of Celtis zenkeri (Ulmaceae). Its four new derivatives (1a–d) and previously reported diacetylated product (1e) have been synthesized and characterized spectroscopically followed by their in vitro screening for anti-urease potential. The diacetylated product (1e) was found to be the most potent inhibitor with an IC50 value of 19.5 ± 0.23 μM compared to thiourea used as standard (21.5 ± 0.47 μM). Furthermore, molecular docking studies were conducted revealing striking interactions of the active compounds with catalytically important residues such as His593, Ala636 and Asp633. Subsequently, the prime MM-GBSA calculations provided the ligand binding and strain energies. The molecular dynamic simulations validated the docked and post-docked complexes where compounds 1b, 1c, 1d and 1e remained stable throughout the simulation. This study provides insight into the N-p-trans-coumaroyltyramine derivatives (1b–e) that can block the substrate entry, thereby inhibiting the urease’s catalytic activity. Hence, these hit compounds can proceed for further pre-clinical studies for drug discovery against urease. Communicated by Ramaswamy H. Sarma

A novel berberine derivative targeting adipocyte differentiation to alleviate TNF-α-induced inflammatory effects and insulin resistance in OP9 cells

Inflammation and insulin resistance play important roles in the development and progression of type 2 diabetes mellitus. The enhancement of adipocyte differentiation can improve insulin sensitivity by increasing glucose uptake, improving insulin signaling, and reducing inflammation. However, only a few adipogenic agents have shown clinical success in patients with type 2 diabetes mellitus. The therapeutic potential of berberine in type 2 diabetes mellitus was confirmed in terms of the target gene-disease relationship using a network pharmacology database prior to synthesizing the derivatives. Novel berberine derivatives were synthesized, and compound 3b promoted adipocyte differentiation and improvement of insulin resistance in OP9 cells. Compound 3b significantly increased the expression of key adipogenic markers including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein β (C/EBPβ) and promoted lipid accumulation without cytotoxicity. Furthermore, tumor necrosis factor α (TNF-α)-induced inhibition of adipocyte differentiation and the elevation of inflammatory responses were reversed by compound 3b. Subsequently glucose uptake level through insulin sensitivity improvement was enhanced by compound 3b. Mechanistically, TNF-α activated mitogen-activated protein kinases (MAPKs): ERK, JNK, and p38, whereas compound 3b attenuated phosphorylation of three MAPKs. Finally, in silico molecular docking suggested the possible binding sites of compound 3b on PPARγ. Collectively, the adipogenic and glucose uptake effects of compound 3b were associated with its anti-inflammatory effects and reduced phosphorylation of MAPKs. These findings suggest that the berberine derivative compound 3b may be a potent antidiabetic agent.

Spectroscopic, DFT, molecular docking and anti-cancer studies of regioselectively designed 1-aryl-indenopyrazoles

L-Proline catalyzed condensation of 1-indanones with DMF-DMA (N,N-dimethylformamide dimethyl acetal) resulted in (Z)-2-((dimethylamino)methylene-2,3-dihydro-1H-inden-1-ones 2 instead of their E-isomers 3, which is further regioselectively transformed into 1-aryl-2,4-dihydroindeno[1,2-c]pyrazole 4 rather than 2-aryl-2,4-dihydroindeno[1,2-c]pyrazoles 5 by condensing with aryl hydrazines. Spectrochemical characterizations and single crystal X-ray diffraction studies were used to resolve syntactic ambiguity between the possible geometric isomers of enaminones (E & Z) and regioisomers 1H-indenopyrazole and 2H-indenopyrazoles. The experimental findings were correlated with computed values and have shown good correlation with the proposed structures. The synthesized indenopyrazoles 4a–f were tested for their ability to inhibit the proliferation of A549 human lung cancer cell lines, and the compound 4b have showed IC50 value 13.77 µM comparable to the reference medication erlotinib (10.26 µM). The complete cell cycle analysis have revealed the accumulation of mitotic cells in G1/S phase. The flow cytometric analysis also revealed the increase in apoptotic cells indicating tumor suppression by the derivative 4b. To get insight into the interactions of the compound and EGFR tyrosine kinase protein molecular docking was performed. Also, pharmacokinetic profiling revealed about the oral compatibility of the synthesized compounds.

Novel citrinin derivatives from fungus Penicillium sp. TW131-64 and their antimicrobial activities.

Six new citrinin derivatives (1, 2, 4, 10, 11, and 16), along with fourteen known analogues, were acquired from Penicillium sp. TW131-64, a marine-derived fungus strain. The chemical structures of new compounds were identified through adopting various spectroscopic methods in combination with X-ray diffraction technology and comparison of the experimental electronic circular dichroism (ECD) with calculated ones. Among them, compounds 1-4 were nitrogen-containing citrinin derivatives existing in enantiomers which were resolved by chiral chromatography. A putative biosynthetic pathway for compounds 1-4 was proposed. Additionally, the antimicrobial activities of these compounds were detected by the broth microdilution assays. Citrinin derivatives 1, 2, 4 and their corresponding enantiomers (1a, 2a, 4a, 1b, 2b, and 4b) exhibited potent antimicrobial activities towards Helicobacter pylori standard strains and multidrug-resistant strains (MIC values ranging from 0.25 to 8μg/mL), which were comparable or even better than metronidazole. Moreover, compounds 1a and 1b also showed remarkable broad antimicrobial effects towards Staphylococcus aureus, Enterococcus faecalis, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, vancomycin-resistant Enterococcus faecium (VRE), and Candida albicans. In summary, our studies demonstrated that citrinin enantiomers 1a-4a and 1b-4b, especially 1a and 1b, can be lead compounds in the research and development (R & D) of novel antimicrobial drugs. KEY POINTS: • 3 novel nitrogen-containing citrinin derivatives (1, 2, 4) were isolated. • citrinin derivatives 1-4 in enantiomers were resolved by chiral chromatography. • citrinin derivatives 1a and 1b showed broad and significant antimicrobial effects.

Identification of novel 4-thiazolidinones as new TcaR inhibitors: Design, synthesis, molecular docking, MD simulation, ADMET and in vitro antibacterial evaluation

Novel morpholine and piperazine-containing 4-thiazolidinone derivatives (6a-6e) and (7a-7e) were designed and synthesized utilizing a multi-component reaction (MCR) to develop lead compounds with excellent antibacterial potency. The synthesized compounds were characterized using various analytical techniques, including 1H NMR, 13C NMR, IR and HR-MS. Additionally, the docking studies against microbial transcriptional regulators (TcaR) protein offered a comprehensive understanding of the binding interactions between potential molecules and the 3KP3 protein of the Staphylococcus epidermidis (RP62A) organism. These docking studies enabled the prediction of the binding affinity and the identification of key molecular interactions between the compounds and the target protein. Derivatives 6b and 6d showed excellent in vitro inhibitory action at par with ampicillin against S. pyogenes and E. coli, respectively. In general, piperazine-containing compounds showed greater affinity to bind with target protein than the morpholine-containing compounds. The probable reason being, the salt bridge is formed using a terminal nitrogen of the piperazine substituent with the target protein. Furthermore, to assess the dynamic behavior and stability of the most promising compound 6b in complex with the target protein, molecular dynamics simulations were conducted. Protein Cα atoms' RMSD figure reveals that the complex was stable throughout the simulation since the deviation was not more than 2.7 Å at any one time. The simulations revealed that the compound maintained its favorable binding conformation throughout the trajectory, indicating a strong and persistent interaction with the target protein. The in silico ADMET studies of synthesized compounds suggest all compounds are nontoxic and non-carcinogenic in the biological systems.

Design, Synthesis and Evaluation of Fluorescent Properties for Benzothiazole Derivatives.

Fluorescence imaging is conducive to establish a bridge between molecular biology and clinical medicine, and provides new tools for disease process research, early diagnosis, and efficacy evaluation, because of the advantages of rapid imaging and nondestructive detection. Herein, a series of fluorescent molecules with thiadiazole, or thiazole, or benzothiazole cores were designed and synthesized to develop more excellent fluorescent molecules in bio-imaging. According to theoretical and experimental methods, we found that benzothiazole derivative 14B with conjugate expansion by (4-aminophenyl) ethynyl group was the most excellent fluorescent molecule among all the investigated compounds and exhibited low cytotoxicity and strong blue and green fluorescence by confocal cell imaging.

Theoretical and experimental investigation of novel quinazoline derivatives: synthesis, photophysical, reactive properties, molecular docking and selective HSA biointeraction

Two new quinazoline derivatives (2a and 2b) were successfully synthesized in this work using the condensation technique in excellent yields. Using spectroscopic techniques and elemental analyses, the compounds were completely characterized. Density functional theory (DFT) computations have been used to examine the title compound’s reactive characteristics. Chemical reactivity was predicted using local reactive descriptors and molecule electrostatic potential. Additionally, Time dependent DFT (TD-DFT) simulations were used to examine the impact of solvents on the photophysical characteristics. The affinity of compounds 2a and 2b for human serum albumin (HSA) was further explored using several electronic spectroscopies. Through static mechanisms, both compounds reduce the intrinsic fluorescence of HSA. It is determined that the HSA-2b complex’s binding constant is significantly greater than the HSA-2a complex. The fluorescence spectrum measurements proved that the HSA underwent structural changes after interaction with these compounds. It was demonstrated by site marker competitive displacement studies that compounds 2a and 2b preferred to bind to site I in HSA subdomain IIA. Additionally, synchronised fluorescence spectra were utilized to analyze how HSA’s conformation changed after interacting with various substances. The molecular docking investigations of these compounds with the three critical HSA binding sites, comprising subdomains IIA, IIIA, and IB, further confirmed the experimental findings. The significant contact between the investigated compounds and HSA was supported by the docking simulations. Communicated by Ramaswamy H. Sarma

Synthesis, in vitro and in silico evaluation of new flavonoids-trifluoroacetylated amino acid conjugates as anti-acetylcholinesterase and anti-proliferative agents

A series of halogenated 3-hydroxyflavones (3HFs) (3a-3f) and their conjugates with two trifluoroacetylated amino acids, namely glycine and L-alanine, were synthesized and characterized by 1H NMR, 13C NMR and ESI-HRMS. All the compounds were evaluated for their ability to inhibit the acetylcholinesterase enzyme and for their anti-proliferative effect against MCF-7, HCT-116 and OVCAR-3 cancer cell lines by standard MTT assay. Most of 3HFs-amino acids conjugates demonstrated promising cytotoxic activities, significantly higher than the corresponding 3HFs. Among them, compounds 8f and 9a showed the best cytotoxic activity against MCF-7 (IC50 = 5.5 and 5.3 µM, respectively), HCT-116 (IC50 = 6.2 and 5.5 µM, respectively) and OVCAR-3 (IC50 = 9.2 and 8.9 µM, respectively). The derivatives 9c and 9b exhibited the highest anti-acetylcholinesterase activity with IC50 values of 50.1 and 55.2 µM, respectively. The structure-activity relationship (SAR) is discussed based on molecular docking simulations.

Preparation and antibacterial activity of coronarin E derivatives

Coronarin E is a main diterpene ever isolated from Hedychium yunnanense. With the aim to enlarge its potential application, four butenolide derivatives (compounds 4a, 4b, 5a and 5b) were obtained from coronarin E via synthetic method, and their antibacterial effects were also evaluated. It is noteworthy that compounds 5a and 5b exhibited stronger antibacterial activities against most of the tested bacterial strains than ampicillin and kanamycin, two first- and second-line antimicrobials in clinical. For example, minimum inhibitory concentration (MIC) of 5a, 5b, ampicillin and kanamycin against Acinetobacter baumanii were 2, 1, 8 and 4 μg/mL, respectively, and MIC of the four compounds mentioned above against Klebsiella pneumonia were 1, 0.5, 16 and 4 μg/mL, respectively. The current studies not only enrich the structural diversity of diterpenes derived from Hedychium genus, but also provide potent candidates for the development of antibacterial medicines.

New tetrahydroisoquinoline-4-carbonitrile derivatives as potent agents against cyclin-dependent kinases, crystal structures, and computational studies

The synthesis of two new hexahydroisoquinoline-4-carbonitrile derivatives (3a and 3b) is reported along with spectroscopic data and their crystal structures. In compound 3a, the intramolecular O—H···O hydrogen bond constraints the acetyl and hydroxyl groups to be syn. In the crystal, inversion dimers are generated by C—H···O hydrogen bonds and are connected into layers parallel to (10–1) by additional C—H···O hydrogen bonds. The layers are stacked with Cl···S contacts 0.17 Å less than the sum of the respective van der Waals radii. The conformation of the compound 3b is partially determined by the intramolecular O—H···O hydrogen bond. A puckering analysis of the tetrahydroisoquinoline unit was performed. In the crystal, O—H···O and C—H···O hydrogen bonds together with C—H···π(ring) interactions form layers parallel to (01–1) which pack with normal van der Waals interactions. To understand the binding efficiency and stability of the title molecules, molecular docking, and 100 ns dynamic simulation analyses were performed with CDK5A1. To rationalize their structure-activity relationship(s), a DFT study at the B3LYP/6-311++G** theoretical level was also done. The 3D Hirshfled surfaces were also taken to investigate the crystal packings of both compounds. In addition, their ADMET properties were explored. Communicated by Ramaswamy H. Sarma

6-Regioisomeric 5,8-quinolinediones as potent CDC25 inhibitors against colorectal cancers

Precise and accurate control of cell cycle progression is required to maintain cell identity and proliferation. Failing to keep it will lead to genome instability and tumorigenesis. Cell Division Cycle 25 (CDC25) phosphatases are the key to regulating the activity of the master cell cycle controller, cyclin-dependent kinases (CDKs). Dysregulation of CDC25 has been shown to associate with several human malignancies. Here, we reported a series of derivatives of the CDC25 inhibitor, NSC663284, bearing quinones as core scaffolds and morpholin alkylamino side chains. Among these derivatives, the cytotoxic activity of the 6-isomer of 5,8-quinolinedione derivatives (6b, 16b, 17b, and 18b) displayed higher potency against colorectal cancer (CRC) cells. Compound 6b possessed the most antiproliferative activity, with IC50 values of 0.59 μM (DLD1) and 0.44 μM (HCT116). The treatment of compound 6b resulted in a remarkable effect on cell cycle progression, blocking S-phase progression in DLD1 cells straight away while slowing S-phase progression and accumulated cells in the G2/M phase in HCT116 cells. Furthermore, we showed that compound 6b inhibited CDK1 dephosphorylation and H4K20 methylation in cells. The treatment with compound 6b induced DNA damage and triggered apoptosis. Our study identifies compound 6b as a potent CDC25 inhibitor that induces genome instability and kills cancer cells through an apoptotic pathway, deserving further investigation to fulfill its candidacy as an anti-CRC agent.

Diestervinyl-functionalized acceptor-acceptor type dithienylethenes with efficient photochromic performance.

Exploring novel dithienylethenes (DTEs) with efficient photochromism has drawn increasing attention in virtue of the potential applications for photoelectric functional materials. In this contribution, we presented two novel acceptor-acceptor (A-A) type DTE derivatives (4a and 4b) by incorporating the diestervinyl moieties with strong electron-withdrawing capacity into two sides of DTE skeleton. The corresponding structures were well confirmed by the NMR (1H and 13C) and HRMS. When irradiated alternately with ultraviolet and visible light, 4a and 4b showed efficient photochromism in toluene, chloroform and DMSO, clearly implying a solvent-dependence feature. Moreover, excellent photoswitching behaviors were also observed in the poly(methyl methacrylate) (PMMA) film. The density functional theory (DFT) calculations suggested that strong Acceptor-Acceptor effect plays a dominative role in the efficient photochromic performance. Hence, this study will provide a useful guidance for developing high-performance DTE derivatives in multi-media.

Synthesis, Molecular Docking, c-Met Inhibitions of 2,2,2-Trichloroethylidene- cyclohexane-1, 3-dione Derivatives Together with their Application as Target SARS-CoV-2 main Protease (Mpro) and as Potential anti-COVID-19.

The lack of anti-COVID-19 treatment to date warrants urgent research into potential therapeutic targets. Virtual drug screening techniques enable the identification of novel compounds that target the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Main Protease (Mpro). The binding of the halogenated compounds to Mpro may inhibit the replication and transcription of SARS-CoV-2 and, ultimately, stop the viral life cycle. In times of dire need for anti- COVID-19 treatment, this study lays the groundwork for further experimental research to investigate these compounds' efficacy and potential medical uses to treat COVID-19. New heterocyclic compounds were synthesized through the first reaction of cyclohexane- 1, 3-dione (1a) or dimedone (1b) with trichloroacetonitrile (2) to give the 2,2,2-trichloroethylidene) cyclohexane-1,3-dione derivatives 3a and 3b, respectively. The latter compounds underwent a series of heterocyclization reactions to produce biologically active compounds. Novel compounds, including fused thiophene, pyrimidine and pyran derivatives, were synthesized and tested against human RNA N7-MTase (hRNMT) and selected viral N7-MTases such as SARS-CoV nsp14 and Vaccinia D1-D12 complex to evaluate their specificity and their molecular modeling was also studied in the aim of producing anti-COVID-19 target molecules. The results showed that compounds 10a, 10b, 10c, 10e, 10f, 10g and 10h showed high % inhibitions against SARs-Covnsp 14. Whereas compounds 5a, 7a, 8b, 10a, 10b, 10c and 10i showed high inhibitions against hRNMT. This study explored the binding affinity of twenty-two halogenated compounds to the SARS-CoV-2 MPro and discovered fifteen compounds with higher binding affinity than Nelfinavir, of which three showed remarkable results. c-Met kinase inhibitions of 10a, 10f, 10g and 10h showed that all compounds exhibited higher inhibitions than the reference Foretinib.

Structure Optimization of 12β-O-γ-Glutamyl Oleanolic Acid Derivatives Resulting in Potent FXR Antagonist/Modulator for NASH Therapy.

The farnesoid X receptor (FXR) plays a crucial role in regulating the metabolism of bile acids, lipids, and sugars. Consequently, it is implicated in the treatment of various diseases, including cholestasis, diabetes, hyperlipidemia, and cancer. The advancement of novel FXR modulators holds immense importance, especially in managing metabolic disorders. In this study, a series of oleanolic acid (OA) derivatives bearing 12β-O-(γ-glutamyl) groups were designed and synthesized. Using a yeast one-hybrid assay, we established a preliminary structure-activity relationship (SAR) and identified the most potent compound, 10b, which selectively antagonizes FXR over other nuclear receptors. Compound 10b can differentially modulate the downstream genes of FXR, including with the upregulation of the CYP7A1 gene. In vivo testing revealed that 10b (100 mg·Kg-1) not only effectively inhibits lipid accumulation in the liver but also prevents liver fibrosis in both BDL rats and HFD mice. Molecular modeling indicated that the branched substitution of 10b extends into the H11-H12 region of FXR-LBD, possibly accounting for its CYP7A1 upregulation, which is different from a known OA 12β-alkonate. These findings suggest that 12-glutamyl OA derivative 10b represents a promising candidate for the treatment of nonalcoholic steatohepatitis (NASH).

Design, synthesis, and biological evaluation of furan-bearing pyrazolo[3,4-b]pyridines as novel inhibitors of CDK2 and P53-MDM2 protein-protein interaction.

The novel series of furan-bearing pyrazolo[3,4-b]pyridines were designed as cyclin-dependent kinase 2 (CDK2) inhibitors and as p53-murine double minute 2(MDM2) inhibitors. The newly synthesized compounds were screened for their antiproliferative activity towardhepatocellular carcinoma (HepG2) and breast cancer (MCF7) cell lines. The most active compounds on both cell lines were additionally evaluated for their in vitro CDK2inhibitory activity. Compounds 7b and 12f displayed enhanced activity (half-maximal inhibitory concentration[IC50 ] = 0.46 and 0.27 µM, respectively) in comparison to the standard roscovitine (IC50 = 1.41 ± 0.03 µM), in addition to, cell cycle arrest at S phase and G1/S transition phase in MCF7 cells treated with both compounds, respectively. Moreover, the most active spiro-oxindole derivative against MCF7 cell line, 16a, exhibited enhanced inhibitory activity against p53-MDM2 interaction in vitro (IC50 = 3.09 ± 0.12 µM) compared to nutlin, and increased the levels of both p53 and p21 by nearly fourfold in comparison to the negative control. Molecular docking studies demonstrated the plausible interaction patterns of the most potent derivatives 17b and 12f in the CDK2 binding pocket and the spiro-oxindole 16a with p53-MDM2 complex, respectively. Consequently, the new chemotypes 7b, 12f, and 16a can be presented as promising antitumor hits for further studies and optimization.

Design, synthesis, biological evaluation, in silico ADME prediction and molecular docking of pyrazole-benzamides as multitargeting protien kinase inhibitors

In the present study, N-(1-(2-bromobenzoyl)-4-cyano-1H-pyrazol-5-yl) halogenated benzamides (5a-h) were prepared and evaluated for their in vitro anticancer activity against three cancer cell lines, namely hepatic cancer (HepG-2), breast cancer (MCF-7) and colon cancer (HCT-116). The derivatives 5a-d and 5 h revealed the most promising growth inhibition effect, with IC50 values ranging from 0.005133 ± 0.000042 to 0.022249 ± 0.000069 μM, compared to doxorubicin, which had IC50 values of 0.004635 ± 0.000002, 0.004587 ± 0.000029, and 0.004064 ± 0.000002 µM respectively. The potential ADME properties of 5a-h were investigated using calculations. Compounds 5a-h have good oral bioavailability and gastrointestinal absorption but cannot penetrate the blood-brain barrier. According to ADME results, 5b has a tumorigenic and reproductive effect. Furthermore, the derivatives 5a, 5b, and 5d produced promising safety profiles on the WI-38 normal cell line with IC50 values of 0.045374 ± 0.002593, 0.115714 ± 0.006732, and 0.058241 ± 0.003411 μM, respectively, compared to doxorubicin, which had IC50 value of 0.038234 ± 0.00223 µM. Moreover, utilizing afatinib and sorafenib as positive controls, compounds 5a, 5b, and 5d were further assessed as in vitro multitargeting candidates towards EGFRWT, VEGFR-2, and B-RAFWT. For the purpose of figuring out potential ligand-protien interactions and stability, in silico molecular docking simulations against VEGFR-2, EGFRWT, and B-RAFWT were run. The results exhibited that compound 5b was the most potent compound, producing an inhibition effect on EGFRWT and B-RAF WT kinases that was approximately equipotent to that obtained by the reference drugs afatinib and sorafenib with IC50 values of 0.000140 ± 0.000009 and 0.000158 ± 0.000009 µM, respectively (IC50 Afatinib: 0.000086 ± 0.000004, IC50 Sorafenib: 0.000097 ± 0.000006) The molecular docking study confirmed the biological result. Moreover, compound 5b arrested the HCT-116 cell cycle at the G1/S phase and showed a good early and late apoptotic induction effect within HCT-116 cells.

Novel [1,2,3]triazoles, [1,2,3]triazolo[4,5-d]Pyrimidines, and Some of Their Glycoside Derivatives: Synthesis and Molecular Modeling as Potential Apoptotic Antitumor Agents

Two new series of 4,5-difunctionalized 1-bromobenzyl[1,2,3]triazole (2a, 3a, 4a, 5a, and 6a) and 4,5-difunctionalized 1-(2-oxo-2-(p-tolylamino)ethyl-[1,2,3]triazole (2b, 3b, 4b, 5b, and 6b) were synthesized using related 1-(azidomethyl)-4-bromobenzene 1a and p-tolylcarbamoyl azide 1b respectively. The substituted [1,2,3]triazolo[4,5-d]pyrimidine-7-one derivatives (7a, 7b, 8a, and 8b) were synthesized by the reaction of [1,2,3]triazolo derivatives 2a and 2b with carbon disulfide in the presence of 10% sodium hydroxide/dimethylformamide and/or by the reaction with formic acid respectively. The S-glucoside derivatives (9–12) of newly synthesized [1,2,3]triazolo[4,5-d]pyrimidines were also synthesized. By using several spectroscopic methods, including IR, 1H NMR, 13C NMR, and elemental analysis, the chemical structures of the novel derivatives were confirmed. The synthetic compounds’ cytotoxicity and in vitro anticancer activity were examined vs. human breast carcinoma (MCF-7), human laryngeal carcinoma (HEP-2), and human colorectal carcinoma (HCT-116) cell lines. According to the findings, HEP-2 and HCT-116 cells are more sensitive to the tested compounds than the other cell lines. In the HEP-2 and MCF-7 cell lines, respectively, compounds 5b and 11 showed potential anticancer activity when compared to the effect of the commonly used anticancer medication, doxorubicin. The selectivity of compounds against the cancer cell line was confirmed by testing their cytotoxicity on VERO (African Green Monkey kidney) normal cells. The anticancer activity of those compounds is suggested to be due to nuclear damage generated by a high generation of reactive oxygen species (ROS). In addition, the induction of apoptosis by significantly upregulating the apoptotic genes PAR-4 and BAX while substantially downregulating the anti-apoptotic genes BCL-2 and BCL-xl. Molecular docking research was undertaken to predict the probable binding poses of the most effective drugs in the active site of CDK-2. The more active compounds (2a, 3a,b, 4a,b, 5a,b, 6b, 11, and 12) have been docked on the CDK-2 enzyme to demonstrate their mode of action as anticancer medicines. The compounds exert many interactions and showed high binding to the CDK-2 receptor. Finally, a hypothetical pharmacophore model was created using the Molecular Operating Environment (MOE) software and five compounds that are structurally similar to the synthesized ones with known anticancer action.

Novel chiral 1,4-bis(β-cyanostyryl)benzene liquid crystals with high circularly polarized luminescence tuned by length of alkyl chains

Although some AIE-based CPL materials had been presented, the design and synthesis novel AIE-based CPL materials and studies on the relationship of structure–property were still a challenging work. Herein, series of novel 1,4-bis(β-cyanostyryl)benzene derivatives 2a, 2b and 2c bearing chiral alkyl chains were prepared, and the influence of length of alkyl chains on CPL properties were investigated for the first time. Samples 2a, 2b and 2c were synthesized by simple procedure with 83–88 % yields. Samples 2b and 2c with longer chains displayed the typical liquid crystalline properties. All of them showed strong fluorescence in both solution and aggregated states. Their chiroptical properties of CD and CPL signals were influenced strongly by the molecular stacking in various states. The self-assembly in mesophase resulted in the best chiroptical properties. The longer alkyl chains contributed to stronger CD and CPL signals. The highest glum value attained 1.6 × 10-2 for sample 2c based on the effective chirality transfer and amplification of liquid-crystalline mesophase.

Design, synthesis, docking study of pyrazolohydrazinopyrimidin-4-one derivatives and their application as antimicrobials.

New series of pyrazoles 4a-c and pyrazolopyrimidines 5a-f had been constructed. The newly synthesized compounds were assessed for their antimicrobial activity towards E. coli and P. aeruginosa (gram -ve bacteria), B. subtilis and S. aureus (gram +ve bacteria) and A. flavus and C. albicans (representative of fungi). The pyrazolylpyrimidine-2,4-dione derivative 5b is the most active candidate against B. subtilis (MIC = 60 µg/mL) and P. aeruginosa (MIC = 45 µg/mL). Regarding antifungal potential, compound 5f was the most effective against A. flavus (MIC= 33 µg/mL). Similarly, compound 5c displayed strong antifungal activity towards C. Albicans (MIC = 36 µg/mL) in reference to amphotericin B (MIC= 60 µg/mL). Finally, the novel compounds had been docked inside dihydropteroate synthase (DHPS) to suggest the binding mode of these compounds.

Abstract 4868: Targeting of ERG positive prostate cancers with ERGi-USU-6 salt derivative

Abstract Introduction: Prostate cancer (PCa) is the second leading cause of cancer deaths among men in the United States. Approximately 50% of patients with PCa harbor an oncogenic TMPRRS2- ERG gene fusion in their primary tumor and 35% of patients with metastatic castration resistant prostate cancers have the gene fusion. We have identified a potent small molecule inhibitor, ERGi-USU-6 salt derivative 7b, that selectively inhibits the growth of ERG positive tumor. This small molecule inhibitor is also effective in inhibiting the growth of benign and cancerous mouse prostate organoids expressing TMPRSS2-ERG (ERG positive organoids). To gain insights into the cancer-selective properties of ERGi-USU-6 salt 7b we evaluated pathways associated in ERGi-USU induced inhibition. Methods: The biological activities of salt derivative 7b, were assessed in hormone- refractory metastatic tumor derived ERG positive prostate cancer cell line, VCaP along with organoids. We monitored the pathways associated in the mechanism of drug action through, cell cycle-regulator proteins by immunoblot assays, cell cycle and ferroptosis related analyses in response to 7b treatment. We also monitored the levels of the RIOK2 kinase, previously shown to bind the parental ERGi-USU compound. The normal primary endothelium derived HUVEC cells were used as normal control due to the normal endogenous expression of ERG in endothelial cells including HUVEC. Results: Cell growth and immunoblot analysis indicated the inhibition of ERG positive prostate organoid upon ERGi-USU treatments resulting in the downregulation of ERG and RIOK2 protein levels. The cell cycle analyses, pathway mapping by protein assessment and ferroptotic assays suggests that salt derivative 7b treatment inhibits the ERG positive prostate cancer through ferroptosis along with RIOK2 inhibition. Conclusions: Our results showed that the ferroptosis inducer ATF3 gene is involved in the cancer-selective activity of ERGi-USU-6 salt derivative 7b. Further, based on our observations we hypothesize that ferroptosis, the iron-dependent form of programmed cell-death, may be the mechanism of cancer selective activity of salt derivative 7b. Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Binil Eldhose, Katherine Beck, Cyrus Eghtedari, Gartrell C. Bowling, Mallesh Pandrala, Sanjay V. Malhotra, Xiaofeng A. Su, Albert Dobi. Targeting of ERG positive prostate cancers with ERGi-USU-6 salt derivative. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4868.