Compounds 3e Research Articles

Novel Schiff bases of quinolin-4(1h)-one: Synthesis, antiproliferative evaluation, apoptosis, cell cycle, autophagy and molecular docking studies in human colon cancer cells

A green and efficient ultrasound-mediated protocol was developed for the synthesis of a series of novel Schiff bases derived from quinoline-4-one. The synthetic strategy involved the condensation of 4-oxo-1,4-dihydro-quinoline-3-carboxaldehyde with diverse anilines and heteroaryl amines. The synthesized compounds were characterized using spectroscopic techniques. A comprehensive in vitro cytotoxicity evaluation against HCT116 and HT-29 human colon cancer cell lines revealed that several compounds exhibited potent anticancer activity. Notably, compounds 3c and 3e demonstrated superior cytotoxicity compared to the clinical standard doxorubicin. Mechanistic studies indicated that these lead compounds induced apoptosis, necrosis, and cell cycle arrest at G1 and G2 phases. Furthermore, autophagy induction was observed. In silico ADMET predictions support the potential of compounds 3c and 3e as promising anticancer drug candidates. The molecular docking studies revealed that the Schiff bases 3c and 3e displayed good interaction with VEGFR-2 receptor. These findings underscore the quinoline-4-one scaffold as a valuable template for the development of novel antitumor agents.

Identification of Imidazo[1,2-a]pyridines-pyrazole-pyran hybrids as Potent Glucose-6-phosphate Dehydrogenase (G6PD) Inhibitors: Synthesis, Molecular docking, DFT studies and ADME prediction

In this study, we aimed to identify new anticancer agents by synthesizing a series of Imidazo[1,2-a]pyridines fused with pyrazole-pyran scaffolds 7a–g in good yields (75–85%) under microwave irradiation. The synthesis was performed through a one-pot, three-component cyclocondensation reaction of 2-(p-substituted)imidazo[1,2-a]pyridine-3-carbaldehyde 4a-g, malononitrile 5, and 5-methyl-2,4-dihydro-3H-pyrazol-3-one 6 in the presence of triethylamine as a catalyst in acetonitrile. The characterization of all synthesized compounds was accomplished through various spectroscopic techniques. All the synthesized compounds were investigated for their anticancer potential in vitro, using an MTT-based assay against A549 lung cancer cell lines. Compounds 7b, 7e, and 7c demonstrated notable anti-proliferative activity against the A549 cell line, while compound 7e showed a significantly lower fluorescence generation (24-fold less) in the G6PD inhibition assay compared to the other compounds.

Design, Synthesis, and Evaluation of Novel Thiazole-Containing Algicides Inspired by Bacillamide A

The pursuit of highly effective, low-toxicity, and eco-friendly algicides for controlling and eradicating harmful algal blooms (HABs) is of paramount importance. The natural allelochemical bacillamide A has displayed impressive algicidal activity against harmful algae with favorable safety profiles. However, the poor synthetic efficiency and large dose requirements of bacillamide A limit its further application. In this paper, 17 thiazole-containing bacillamide derivatives (BDs) were designed and synthesized in three linear steps as potential algicides. Eight compounds (6a, 6c, 6j, 7b, 7c, 7d, 7e, and 7g) displayed potent inhibitory effects against Prorocentrum minimum, Skeletonema costatum, and Alexandrium pacificum, and they had similar or better activity than the positive control (CuSO4) and bacillamide A. Compound 6a exhibited the most potent algicidal activity against S. costatum (half-maximal effective concentration [EC50] = 0.11 μg/mL), being 23-fold more potent than bacillamide A, 28-fold more potent than CuSO4, and 39-fold more potent than Diuron. Compound 6j exhibited significant algicidal activity against the toxic dinoflagellates P. minimum (EC50 = 1.0 μg/mL) and A. pacificum (EC50 = 0.47 μg/mL), being 3–5-fold more potent than natural bacillamide A, Diuron, and CuSO4. Micrographs and SEM images revealed that 6j induced cell wall rupture and cellular content leakage. Biochemical and physiological studies indicated that 6j might partially disrupt the antioxidant and photosynthetic systems in algal cells, resulting in morphological changes, cell wall rupture, and inclusion leakage. Our work suggests that 6j has a distinct mode of action from CuSO4 and provides a promising candidate for the development of new algicides, worthy of further investigation.

Synthesis of Paracetamol‐Appended Bis 1,2,3‐Triazole Analogues as Anti‐Inflammatory Agents

AbstractParacetamol‐based bis 1,2,3‐triazole analogues were synthesized involving copper‐catalyzed click chemistry protocol. The new compounds were characterized by 1H NMR, 13C NMR, and mass spectral techniques. All the compounds were evaluated for their in vitro anti‐inflammatory properties using diclofenac as standard reference. The compound 6b with chlorine and fluorine functions displayed outstanding activity with IC50 values of 7.34 ± 0.45 µM and 7.84 ± 0.47 µM, respectively. Compound 6g with methyl and fluorine functions displayed best activity with IC50 values of 9.34 ± 0.22 µM and 9.40 ± 0.35 µM, respectively. Compound 6i, 6k, 6f, 6a, 6e, 6h, 6j, and 6l exhibited promising activity with respect to diclofenac. Using PyRx tool, the molecular docking study against crystal structure of COX‐2 proved the binding efficacies with notable binding interactions.

First Report on Cationic Triphenylphosphonium Compounds as Mitochondriotropic H3R Ligands with Antioxidant Properties

Neurodegenerative diseases are a major public health problem due to the aging population and multifaceted pathology; therefore, the search for new therapeutic alternatives is of the utmost importance. In this sense, a series of six 1-(3-phenoxypropyl)piperidines alkyl-linked to a triphenylphosphonium cation derivative were synthesized as H3R ligands with antioxidant properties to regulate excessive mitochondrial oxidative stress and contribute to potential new therapeutic approaches for neurodegenerative diseases. Radioligand displacement studies revealed high affinity for H3R with Ki values in the low to moderate two-digit nanomolar range for all compounds. Compound 6e showed the highest affinity (Ki H3R = 14.1 nM), comparable to that of pitolisant. Antioxidative effects were evaluated as radical-scavenging properties using the ORAC assay, in which all derivatives showed low to moderate activity. On the other hand, cytotoxic effects in SH-SY5Y neuroblastoma cells were investigated using the colorimetric alamar blue assay, which revealed significant effects on cell viability with an unequivocally structure–toxicity relationship. Finally, docking and molecular simulation studies were used to determine the H3R binding form, which will allow us to further modify the compounds to establish a robust structure-activity relationship and find a lead compound with therapeutic utility in neurodegenerative diseases.

Bioisosteric Replacement in the Search for Biologically Active Compounds: Design, Synthesis and Anti-Inflammatory Activity of Novel [1,2,4]triazino[2,3-c]quinazolines

Background: Designing novel biologically active compounds with anti-inflammatory properties based on condensed quinazolines is a significant area of interest in modern medicinal chemistry. In the present study, we describe the development of promising new bioactive molecules through the bioisosteric replacement of a carbon atom with a sulfur atom in anti-inflammatory agents, specifically 3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)butanoate. Methods: Design and synthetic studies have led to the series of previously unknown substituted 2-[((3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)methyl)thio]carboxylic acids and their esters. These compounds were synthesized by reacting 6-chloroalkyl-3-R-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones with sulfanylalkyl carboxylic acids and their functional derivatives. The purity and structure of the obtained compounds were confirmed using a set of physicochemical methods, including elemental analysis, HPLC-MS, and 1H NMR spectroscopy. Molecular modeling, predicted toxicity, drug-likeness, and pharmacokinetics data were used to select compounds for evaluation of their effects on acute aseptic inflammation (carrageenan-induced paw edema test) and on markers of the inflammatory process. Results: The compound 2-((1-(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)ethyl)thio)acetic acid (compound 2e) was identified as the most active anti-inflammatory agent (AA = 53.41%), demonstrating significant inhibition of both paw edema development and the generation of pro-inflammatory cytokines and mediators. Conclusions: Results from docking studies and analysis of “structure-affinity” correlations revealed that these compounds are promising candidates for further modification and detailed investigation of their anti-inflammatory activity

Semi-Preparation and X-ray Single-Crystal Structures of Sophocarpine-Based Isoxazoline Derivatives and Their Pesticidal Effects and Toxicology Study.

Recently, research and development of novel pesticides from natural plant products have received much attention. To accelerate the application of sophocarpine as the agrochemical candidate, a series of novel sophocarpine-based isoxazoline derivatives were prepared by the 1,3-dipolar [2 + 3] cycloaddition reaction of sophocarpine with different chloroximes. Their structures were well characterized by high-resolution mass spectra, infrared spectra, and proton/carbon-13 nuclear magnetic resonance spectra. Eight steric configurations of compounds 5a, 5e', 5f, 5g, 5h, 5i, 5r, and 5u' were further determined by X-ray single-crystallography. Against Aphis citricola Van der Goot, compounds 5n (LD50: 0.032 μg/nymph) and 5o (LD50: 0.024 μg/nymph) exhibited greater than 3.7- and 4.9-fold potent aphicidal activity compared to sophocarpine (LD50: 0.118 μg/nymph). Against Tetranychus cinnabarinus Boisduval, derivative 5g displayed the most promising acaricidal activity with the LC50 value of 0.247 mg/mL, which was 14.2-fold that of sophocarpine. Compounds 5d and 5g also exhibited good control efficacy against T. cinnabarinus. Scanning electron microscopy images indicated that compound 5g can destroy the mite cuticle layer. These results will provide the foundation for the structural modification and use of sophocarpine derivatives as agrochemicals in the future.

Anti-cancer Activity Evaluation of Naphthalenonic and Chromanonic Spiroisoxazoline Derivatives as Selective COX-2 Inhibitors on HT29 Cell Lines

Background: Cyclooxygenase-2 (COX-2) is induced in response to proinflammatory conditions, and it is not only a key enzyme in the inflammatory process, but also seems to be highly expressed in various types of cancer cells. On the other hand, it is well documented that chemical compounds with spiro scaffolds in their structure could be effective chemical agents against cancer types. Objective: In this study, the cytotoxicity effects of spiroisoxazoline derivatives containing naphthalinone and chromanone spiro-bridge were investigated. Methods: The cytotoxicity effects of compounds 7a-7h were evaluated by performing the MTT assay on the HT-29 (colorectal cancer), MCF-7 (breast cancer), and HEK-293 (normal kidney) cell lines. After that, a compound with high yield and remarkable cytotoxic activity was selected to analyze the cell cycle and apoptosis mechanism. Results: The most effective cytotoxic activity was observed on HT-29 and MCF-7 cell lines of compounds 7b (IC50 value: 1.07±0.28 µM) and 7f (IC50 value: 11.92±1.07 µM). None of the compounds had a toxic effect on normal HEK-293 cells, except for compound 7g with an IC50 value of 21.30±16.14 µM, whose effect was much lower than that of cisplatin and doxorubicin, known as anti-cancer agents. Subsequently, compound 7e with significant yield and cytotoxic activity was investigated to evaluate cell cycle and apoptosis. The result showed that compound 7e induced significant G0/G1 cell cycle arrest and apoptosis in HT-29 cells Conclusion: The selective COX-2 inhibitor compounds with spiroisoxazoline core structure could be suitable scaffolds for cytotoxic effects.

Synthesis and Molecular Docking of Curcumin-Derived Pyrazole-Thiazole Hybrids as Potent α-Glucosidase Inhibitors.

α Glucosidase inhibitors are critical for diabetes management, with pyrazoles and thiazoles emerging as effective options. This research highlights curcumin-based pyrazole-thiazole hybrids as potential inhibitors, synthesizing derivatives and evaluating their inhibitory capabilities. The study involved the synthesis of novel compounds using hydrazonoyl halides, confirmed through elemental and spectral analyses. The synthesized derivatives exhibited significant α-glucosidase inhibition, with IC50 values ranging from 3.37 ± 0.25 to 16.35 ± 0.37 µM. Among them, compound 7e demonstrated the strongest inhibition at 3.37 ± 0.25 µM, outperforming the standard drug acarbose (IC50 = 5.36 ± 0.31 µM). In silico assessments and molecular docking using AutoDock Vina revealed strong interactions, particularly with compounds 7b, 7e, 7f, and 7g, indicating their potential as stable and effective inhibitors. The results suggest that the synthesized pyrazole-thiazole hybrids hold promise as novel therapeutic agents for diabetes, warranting further exploration of their substituent effects for optimized inhibitor design.

In-vitro and in-silico studies based discovery of 2-aryl-N-(4-morpholinophenyl)thiazol-4-amines as promising DNA gyrase inhibitors

Background: DNA gyrase is an important enzyme for the survival of bacteria. Many DNA gyrase inhibitors are in clinical practice. However, these inhibitors also encompass certain toxic and drug/food interactions. This warrants the development of a new template as DNA gyrase inhibitors. Therefore, this study aimed to deliver morpholine-based thiazoles (5a-5l) as safer DNA gyrase inhibitors.Methods: The 5a-5l were prepared by reacting compound 3 with various aryl thioamides. The structures of 5a-5l were ascertained by their spectral records. The 5a-5l were subjected to their antibacterial activity potential (serial plate dilution method), DNA gyrase inhibiting activity, and toxicity analysis (MTT assay) against HepG2 & Vero cell lines. The in-silico studies (pharmacokinetic parameters and molecular docking) of 5a-5l were likewise performed.Results: It was surprisingly observed that the MIC values of 5a-5l were equal to the MIC values of ciprofloxacin (12.5 µg/ml) against the tested bacteria, whereas the DNA gyrase inhibitory activity (IC50 in µg/ml) of 5h (3.52), 5g (3.76), 5f (3.88), 5e (4.08), 5l (4.11), 5b (4.28), 5k (4.28), 5i (4.30), and 5d (4.32) was equal/better than ciprofloxacin (4.32). The MTT assay also implied the non-cytotoxic nature of 5a-5l against HepG2 & Vero cell lines up to 200 µg/ml concentration. The docking outcomes indicated a similar binding pattern of 5a-5l and ciprofloxacin at the active site of DNA gyrase, wherein 5a-5l displayed a better binding affinity for the active site. The in-silico toxicity data employing the ProTox-II web server indicated no hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, or cytotoxic effect of 5a-5l. Also, the SwissADME software supported the drug-likeliness properties and high gastrointestinal absorption of 5a-5l.Conclusion: Compounds 5h, 5g, 5f, 5e, 5l, 5b, 5k, 5i, and 5d are potent DNA gyrase inhibitors with promising safety profiles.Keywords: Discovery; Morpholine; Thiazole; DNA gyrase; MTT assay; Docking

Synthesis and Biological Evaluation of Isoaurone Derivatives as Anti-inflammatory Agents.

Twenty-eight isoaurone derivatives with 1,2,4-triazole moieties were synthesized using a fragment-based design strategy, and their anti-inflammatory activity was investigated. The anti-inflammatory effect of the most active derivatives, 14e (41.82%), was dose-dependent and higher than the values for celecoxib (31.82%). Compound 14e was almost non-toxic and inhibited different concentrations of nitric oxide (NO). The western blotting results demonstrated that cyclooxygenase-2 (COX-2) expression was elevated when the macrophages were exclusively treated with LPS. However, compound 14e effectively suppressed the LPS-induced COX-2 upregulation. Subsequent investigation revealed that 14e is a promising compound capable of inhibiting the downstream signaling of COX-2. With the above interesting biological profile, molecular 14e could be a promising lead to develop novel anti-inflammatory agents.

Synthesis and biological evaluation of 1, 2, 3-triazole incorporated pyrrole derivatives as anticancer agents

A new series of 1,2,3-triazole skeleton incorporated pyrrole derivatives (11a–j) were developed and their chemical structures were confirmed by analytical data. Further, the anticancer profile of these newly derived compounds 11a–j was assessed against four types of human cancer cell lines such as human breast cancer (MCF-7), lung cancer (A549), colon cancer (Colo-205) and ovarian cancer (A2780) by employing of the MTT method and was compared with etoposide used as a positive control. Most of the examined derivatives displayed moderate to good activity compared with the positive control. Among them, five compounds 11a, 11b, 11c, 11d, and 11e showed more potent activity. Particularly, compound 11a showed superior activity.

One-pot synthesis of fused isoxazolo[4′,5′:4,5]thiopyrano[2,3-d]pyrimidines as potent EGFR targeting anti-lung cancer agents

The requirement for scaffolds has prompted synthetic chemists to devise simple and effective methods for optimal synthesis, which are critical in the medical industry. Under comparatively optimized conditions, a click followed by a CC bond coupling reaction between iodoalkyne (4) and substituted nitrile oxide was utilized to explore the synthesis of fused isoxazoles containing thiopyrano[2,3-d]pyrimidine under microwave irradiation. The synthesized compounds were tested for their anticancer activity against EGFR wild-type human non-small cell lung cancer cells (NCI-H460 and A549). The compounds 6i and 6l have shown more potent activity against both cancer cell lines as compared to standard drugs doxorubicin and erlotinib. And also compounds 6e, 6j, and 6k have shown more potent activity as compared to Doxorubicin and moderate activity compared to erlotinib. Later, in vitro EGFR results of more potent compounds revealed that compounds 6l and 6k have shown potent EGFR activity compared to standard erlotinib. To evaluate the molecular interactions of more potent compounds with the human epidermal growth factor receptor. It was observed that all the potent compounds exhibited greater binding energies in comparison to the standard drug erlotinib.

Acetic acid-driven one-pot synthesis of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides and Pharmacological Evaluations.

A diverse set of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides 4(a-o) were synthesized via a one-pot reaction of 5-amino[1,2,3]thiadiazole, various aromatic aldehydes, and different acetoacetanilides, using glacial acetic acid as the solvent and without the need for any catalysts. The resulting compounds were obtained in moderate to good yields. All the newly synthesized compounds were evaluated for their antimicrobial activity. Among them, compound 4e demonstrated superior efficacy against Salinivibrio proteolyticus strain of Gram-(-Ve)-bacteria compared to ciprofloxacin. Compound 4d exhibited the highest potency against the fungal strain Candida albicans surpassing Amphotericin B. 4d and 4e's physicochemical characteristics were assessed. According to docking analysis, DHTDAPy 4e shows the higher binding affinity of -7.2 kcal moL-1 in the binding cavity of the receptor. These findings illustrate the safety and tolerability as well as the potency of newly syntehsized DHTDAPy against the fungal and bacterial infections.

Novel α-Cyano-Indolyl Chalcones as Anti-Cancer Candidates, Induce G1/S Cell Cycle Arrest and Sequentially Activate Caspases-7, 8, and 9 in Breast Carcinoma

Six substituted α-cyano-indolylchalcones have been prepared and their structures were verified by various spectral analysis tools. Compared with the standard drug 5-Fluorouracil) 5-FU(, the anticancer activity against prostate cancer (PC3) and breast cancer cell line (MCF7) was determined using the cytotoxic MTT assay. Also, the cytotoxic effect against normal melanocytes (HFB4) was studied to detect the selectivity of the compounds. Among the series, compound 3e was the most active and selective one toward MCF7 (IC50= 0.18 µmole/mL, SI= 7.6). In silico studies were performed to demonstrate the inhibitory effect of compound 3e on EGFRK, CDK2, and MDM2 domains. Different molecular techniques were performed to know the efficacy of the novel 3e on apoptotic death of breast carcinoma cells.

Synthesis, optimization and antitumor activity evaluation of sulfonyl benzoyl hydrazide derivatives as novel human LSD1 inhibitors

A new set of compounds known as sulfonyl benzoyl hydrazide derivatives were synthesized and tested using cellular assays. Through systematic optimization starting from general structure S-1, compound 10e emerged as highly promising. It exhibited potent inhibitory activity with an IC50 value of 0.8 nM and possessed moderate clogP. Compounds 10e significantly inhibited solid tumor cells proliferation. Additionally, 10e induced apoptosis and arrested the cell cycle. Furthermore, in vivo studies using an HCT116 xenograft model showed substantial growth inhibition of tumors, accompanied by a favorable safety profile. These findings underscored compound 10e as a novel LSD1 inhibitor with robust efficacy both in vitro and in vivo, establishing it as a promising lead compound for further anticancer drug development.

Synthesis, spectroscopic characterization, DFT analysis, antibacterial, antifungal, antioxidant, molecular docking, and ADME study of 3,4-dihydro-2H-napthalen-1-one tagged chalcone derivatives

Chalcone derivatives were synthesized from 3,4-dihydro-2H-naphthalen-1-one using a base-catalyzed Claisen-Schmidt reaction and characterized by FT-IR, ¹H NMR, and ¹³C NMR spectroscopy. Density functional theory (DFT) with the B3LYP/6-311G(d,p) basis set was employed to explore the structural, electronic, and quantum properties of the compounds. Simulated electronic absorption spectra for compounds 3c and 3e in gas phase, DMSO, and DCM were generated using time-dependent DFT (TD-DFT). Compound 3c's first singlet excited state shifted from 376.10 nm in the gas phase to 390.08 nm in DMSO, while compound 3e shifted from 381.58 nm to 383.54 nm in DMSO. Experimental absorption values matched the theoretical predictions, with higher oscillator strengths in DMSO and DCM indicating solvent-enhanced transition probabilities. The antimicrobial activity of the chalcones was evaluated against four bacterial strains (E. coli, B. subtilis, S. aureus, and Streptococcus spp.) and four fungal strains (R. oryzae, P. chrysogenum, A. niger, and C. albicans). Compounds 3d and 3f showed strong antibacterial activity with MIC values of 3.9 µg/mL and moderate antifungal activity. Antioxidant properties were assessed using DPPH and hydroxyl radical assays, with compound 3d demonstrating 75.8 % and 76.4 % scavenging activity for OH and DPPH radicals, respectively. ADME studies were conducted to evaluate pharmacokinetics, and molecular docking studies revealed strong binding affinities. Compounds 3a and 3e had docking scores of -8.7 kcal/mol with the E. coli protein (PDB ID: 1KZN), while 3d and 3f performed best against B. subtilis (PDB ID: 1BAG) and S. aureus gyrase (PDB ID: 2XCT), with scores of -9.1 and -8.3 kcal/mol, respectively. Molecular dynamics simulation of compound 3d with 1BAG over 100 ns confirmed stable binding. These findings suggest chalcone derivatives have strong potential for pharmaceutical development.

Screening of synthesized perimidine compounds for the assessment of antimicrobial potential: in-vitro and in-silico molecular docking and molecular dynamics simulation studies

Presently, antimicrobial resistance is a major and worldwide concern due to high rate of mutation in microorganisms, widespread use, lack of efficacy of drugs, and low drug discovery rate. Considering the importance of N-heterocycles as antibiotics, perimidine derivatives 3(a–v) have been synthesized via cyclocondensation reaction of 1,8-diaminonaphthalene and aryl aldehydes. Further, the synthesized perimidines 3(a–v) were screened as potent antimicrobial agents via in-vitro, in-silico, ADME and MD simulation studies. All 22 derivatives 3(a–v) were studied against two-gram +ve (E. coli and P. aeruginosa), two-gram −ve (S. aureus and B. subtilis), and two fungal (A. niger and S. cerevisiae) strains using ciprofloxacin and fluconazole as reference drugs. The in-vitro study results showed that compounds 3e, 3h, 3l, and 3m were the most potent against S. aureus and 3(a–d), 3(g–i), and 3s were the most active against B. subtilis as compared to the standard. Furthermore, molecular docking studies were performed against Dihydrofolate reductase (PDB Id: 3SRW) from S. aureus, DNA gyrase (PDB Id: 4DUH) from E. coli, and ERG11 gene (PDB Id: 4LXJ). Compounds 3f, 3f/3m, and 3o were found to bind efficiently with the highest binding energy − 10.6, − 9.6, and − 11.3kcal/mol depicting the potential inhibitor of 3SRW, 4DUH, and 4LXJ receptor protein, respectively. The drug-likeness properties of compounds were studied using SwissADME program. To further validate these findings, molecular dynamics simulations were conducted to evaluate their binding stability. From simulation studies, it was observed that all the shortlisted compounds displayed stable binding within the active site of the selected proteins.Graphical abstract

1,4-Naphthoquinone thiazoles: Synthesis, crystal structure, anti-proliferative activity, and inverse molecular docking study

In this study, 1,4-naphthoquinone thiazole hybrids were synthesized by reacting 1,4-naphthoquinone thioureas with various α-bromoketones in 78–86 % yields and characterized using 1H NMR, 13C NMR, FT-IR, and HRMS techniques. Furthermore, single crystal x-ray diffraction studies were also performed for 3b and 3c hybrids to determine stereochemistry. Density Functional Theory (DFT) calculations were performed to obtain additional information and to support the x-ray studies. The in vitro anti-proliferative activities of 1,4-naphthoquinone thiazoles were investigated against PC3 human prostate cancer cells. The products 3a–h showed anti-proliferative activity against PC3 cells, and the cell viability studies showed that the IC50 values of compounds 3f and 3e were 20.10 µM and 21.14 µM, respectively, while the other compounds exhibited lesser cytotoxic effects than the former two. Potential target underlying the mechanism of action of the synthesized compounds against prostate cancer was identified using inverse (reverse) docking method. Molecular dynamics simulation was also conducted to confirm the stability of the 3f/enzyme system. It was determined that the solubility in ethanol was better for compounds bearing methyl substituent on X1 location than compounds containing tert‑butyl on the same location. Compounds with F atom on X2 position were more soluble than the others in the corresponding groups.

Development of selective heterocyclic PDE4 inhibitors for treatment of psoriasis

Psoriasis is a chronic autoimmune disease that badly affects the life quality of patients and their families. Inadequate efficacy, safety risks, high cost and low compliance of current psoriasis drugs urge development of novel small molecular drugs. In this study, two series of 37 novel compounds were designed and synthesized as inhibitors of phosphodiesterase 4 (PDE4) that specifically hydrolyzes second messenger cAMP and is an effective target for treatment of inflammatory diseases. Comprehensive structural-activity optimization led to finding of inhibitor 2e with IC50 = 2.4 nM for PDE4D and >4100-fold selectivity over other PDE families. Compound 2e inhibited the release of TNF-α (IC50 = 21.36 μM) and IL-6 (IC50 = 29.22 μM) in the LPS-stimulated Raw264.7 cells. Topical application of 2e exhibited remarkable therapeutic efficacy in imiquimod-induced psoriasis mice model, suggesting that 2e is a strong drug candidate for treatment of psoriasis.