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Introduction: Isatin, a heterocycle scaffold, is the backbone of many anticancer drugs and has previously been reported to engage multiple cellular targets and mechanisms, including angiogenesis, cell cycle, checkpoint pathways and multiple kinases. Here, we report that a novel isatin derivative, 5i, degrades estrogen receptor alpha (ERα) in estrogen-dependent breast cancer cells. This effect of the isatin nucleus has not been previously reported. Tamoxifen and fulvestrant represent standard therapy options in estrogen-mediated disease but have their own limitations. Isatin-based triple angiokinase inhibitor BIBF1120 (Nintedanib) and multikinase inhibitor Sunitinib (Sutent) have been approved by the FDA. Methods: Keeping this in view, we synthesized a series of N'-(1-benzyl-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) hydrazide derivatives and evaluated them in vitro for antiproliferative activities in MCF-7 (ER+) cell line. We further investigated the effect of the most potent compound (5i) on the Erα through Western Blot Analysis. We used in silico pharmacokinetics prediction tools, particularly pkCSM tool, to assess the activity profiles of the compounds. Results and discussion: Compound 5i showed the best antiproliferative activity (IC50 value; 9.29 ± 0.97 µM) in these cells. Furthermore, 5i downregulated ERα protein levels in a dose-dependent manner in MCF-7. A multifaceted analysis of physicochemical properties through Data Warrior software revealed some prominent drug-like features of the synthesized compounds. The docking studies predicted the binding of ligands (compounds) with the target protein (ERα). Finally, molecular dynamics (MD) simulations indicated stable behavior of the protein-ligand complex between ERα and its ligand 5i. Overall, these results suggest that the new isatin derivative 5i holds promise as a new ERα degrader.
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Many non-steroidal anti-inflammatory drugs (NSAIDs) concurrently inhibit both COX-1 and COX-2, with a preference for specifically targeting COX-2 due to its significant involvement in various pathologies. In addition to COX enzymes, several other targets, including Aldose reductase, Aldo-ketoreductase family 1-member C2, and Phospholipase A2, have been identified as contributors to inflammation and a myriad of other diseases. In this context, a series of 2-substituted benzimidazole derivatives was synthesized and assessed for their anti-inflammatory potential through both in vitro and in vivo assays. Molecular docking studies were conducted to elucidate the mechanism of action of these compounds against COX enzymes and other therapeutic targets associated with NSAIDs, such as Aldose reductase, AIKRC, and Phospholipase A2. Among the synthesized compounds, B2, B4, B7, and B8 demonstrated IC50 values lower than the standard ibuprofen, as determined by the Luminol-enhanced chemiluminescence assay. Validation of these findings was achieved through an in vivo carrageenan-induced mice paw edema model, confirming a comparable anti-inflammatory effect to diclofenac sodium observed in vitro. Notably, these compounds exhibited significant binding affinity with all therapeutic targets investigated in this study. These results suggest that the newly synthesized derivatives possess noteworthy anti-inflammatory potential, warranting further exploration for the development of novel multi-targeting inhibitors.
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The objectives of the study were to conduct phytochemical screening of crude extracts of Cissampelos pareira L. and Lantana camara L. and assessing their biological potentials against protein kinase enzymes, followed by the evaluation of antioxidant and antimicrobial capacities. The n-hexane (A-Ð, B-Ð) and ethyl extracts (A-ÐÐ, B-ÐÐ) displayed moderate to good antioxidant activity, while the methanol fractions (A-ÐÐÐ, B-ÐÐÐ) showed significant antioxidant activity. Among all the three crude extracts, the ethyl acetate extract (B-II) of L. camara exhibited significant protein kinase inhibitions with remarkable antioxidant potential and was therefore purified through column chromatography. Fraction B-ÐÐ-2 showed the highest flavonoid contents (735.43), with the most promising protein kinase inhibition exerted by the subtractions B-ÐÐ-2, B-ÐÐ-3, B-ÐÐ-4, and B-ÐÐ-7. Hence, active fractions were examined through GC-MS for the identification of active constituents, revealing 17 active compounds. In the case of Lantana camara, the ethyl acetate crude extract along with fractions led to the identification of more than thirty compounds, which may be further explored to find a potential lead for drug development.
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Heterocyclic compounds with oxazole and imidazole rings in their structure have disclosed momentous biological aptitudes. Taking into account their superlative attributes, the present study was designed to introduce a new synthetic scheme to make new derivatives with tremendous futuristic pharmacological potentialities. Series of Oxazolones were synthesized by using substituted benzaldehyde with benzyl halides to produce respective benzaldehyde derivatives 1 (a-d) which further reacted with hippuric acid to yield oxazolones 2 (a-e). Newly synthesized oxazolones then reacted with 4-chloroaniline to yield corresponding imidazolones 3 (a-e). All the compounds were characterized by using FTIR and NMR spectroscopic techniques. Docking studies of Compounds were conducted using AutoDock Vina and analyzed with PYMOL. All synthesized oxazolone and imidazolone derivatives exhibited antioxidant potential, demonstrated by their IC50 values compared to ascorbic acid standard. Oxazolone derivatives (2a-2e) exhibited good acetyl cholinesterase inhibitory potential whereas Imidazolone series did not show significant inhibition as shown by their IC50 values compared to donepezil as a standard. Docking studies of all compounds against acetylcholinesterase demonstrated favorable binding affinity, indicating their potential for further in-vivo studies. It is notable that novel compounds of both oxazolones and Imidazolone series exhibited antioxidant potential with maximum percentage inhibition of 75.9 (IC50 12.9 ± 0.0573 µM/mL) by compound 2d while compound 2a showed AChE inhibitory potential with maximum %age inhibition of 75.49 (IC50 7.8 ± 0.0218 µM/mL).Communicated by Ramaswamy H. Sarma.
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Methotrexate (MTX)-induced intestinal mucositis (IM) is a common side effect in cancer treatment that impairs the immune system and gut microbes, resulting in loss of mucosal integrity and gut barrier dysfunction. The quality of life and outcomes of treatment are compromised by IM. The present study was designed to investigate the mucoprotective potential of the benzimidazole derivative N-{4-[2-(4-methoxyphenyl)-1H-benzimidazole-1-sulfonyl] phenyl} acetamide (B8) on MTX-induced IM in mice. IM was induced by a single dose of MTX in mice and assessed by physical manifestations as well as biochemical, oxidative, histological, and inflammatory parameters. B8 (1, 3, 9 mg/kg) significantly reduced diarrhea score, mitigated weight loss, increased feed intake and, survival rate in a dose-dependent manner. Notably, B8 exhibited a mucoprotective effect evident through the mitigation of villus atrophy, crypt hypoplasia, diminished crypt mitotic figures, mucin depletion, and oxidative stress markers (GSH, SOD, MDA, and catalase concentration). Gene expression analysis revealed that B8 downregulated the mRNA expression of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), IL-1ß, and nuclear factor-κB (NF-κB) and concurrently upregulated IL-10 expression in contrast to the MTX group. Further, B8 significantly improved the luminal microflora profile by augmenting the growth of Lactobacillus spp. and reducing the number of pathogenic bacteria (E. coli). Additionally, the enzyme-linked immunoassay showed that B8 decreased the levels of pro-inflammatory cytokines. Our findings suggest that B8 had mucoprotective effects against MTX-induced IM and could be used as an adjunct in chemotherapy to deter this side effect.
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Heterocyclic amines and acetamide derivatives are known for their chemotherapeutic potential. Hence, in the present study, morpholine was taken as a principal product and novel morpholine derivatives were designed, formulated, characterized, and screened for the mechanism of inhibition of carbonic anhydrase and their anticancer potential. In addition, in vitro inhibition of hypoxia-inducible factor-1 (HIF-1) protein was also investigated. Results revealed that compounds 1c, 1d, and 1h possessed significant inhibitory activities against carbonic anhydrase with IC50 of 8.80, 11.13, and 8.12 µM, respectively. Interestingly, the carbonic anhydrase inhibitory activity of compound 1h was comparable with that of standard acetazolamide (IC50 7.51 µM). The compounds 1h and 1i significantly inhibited the proliferation of ovarian cancer cell line ID8 with IC50 of 9.40, and 11.2 µM, respectively while the standard cisplatin exhibited an IC50 8.50 µM. In addition, compounds 1c, 1b, 1h and 1i also exhibited significant inhibitory effects on HIF-1α. In conclusion, we report first time the biological potential of morpholine based compounds against ovarian cancer and HIF-1α that may serve as lead molecules for drug discovery.
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Heterocyclic nuclei have shown a wide variety of biological activities, highlighting their importance in drug discovery. Derivatives of 2,4-subsituted thiazolidine have a structural similarity with the substrates of tyrosinase enzymes. Hence, they can be used as an inhibitor to compete against tyrosine in the biosynthesis of melanin. This study is focused on design, synthesis, biological activities, and in silico studies of thiazolidine derivatives substituted at positions 2 and 4. The synthesized compounds were evaluated to determine the antioxidant activity and tyrosine inhibitory potential using mushroom tyrosinase. The most potent tyrosinase enzyme inhibitor was compound 3c having IC50 value 16.5 ± 0.37 µM, whereas compound 3d showed maximum antioxidant activity in a DPPH free radical scavenging assay (IC50 = 18.17 µg/mL). Molecular docking studies were conducted using mushroom tyrosinase (PDB ID: 2Y9X) to analyze binding affinities and binding interactions of the protein-ligand complex. Docking results indicated that hydrogen bonds and hydrophobic interactions were mainly involved in the ligand and protein complex. The highest binding affinity was found to be -8.4 Kcal/mol. These results suggest that thiazolidine-4-carboxamide derivatives could serve as lead molecules for development of novel potential tyrosinase inhibitors.
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A new class of azole-derived hemiaminal ethers is designed as acetylcholinesterase (AChE) inhibitors. The synthesized compounds exhibited remarkable inhibitory activity against acetylcholine. Chiral hemiaminals (3d and 3i) based on (R)-menthoxymethyl group exhibit excellent inhibition with IC50 values of 0.983 ± 1.41 and 1.154 ± 0.89 µM. Similarly, butoxymethyl derivatives 3a, 3f and 3h, also showed promising inhibition comparable to the standard drug, Donepezil. In silico studies were performed to understand the mode of interactions with the target proteins, where menthoxymethyl azoles 3d and 3i demonstrated the highest docking scores. Molecular dynamics simulations displayed the stable ligand-protein complex of 3i with effective binding interactions. The bioavailability and pharmacokinetic parameterssupported the suitability of these small molecule inhibitors to develop cost-effective drug leads for Alzheimer's disease (AD). MTT assay substantiated the non-cytotoxic nature of the compounds. The synthesized compounds are extensively characterized by 1H NMR, 13C NMR and mass spectral data and SC-XRD.Communicated by Ramaswamy H. Sarma.
Subject(s)
Alzheimer Disease , Cholinesterase Inhibitors , Humans , Cholinesterase Inhibitors/chemistry , Acetylcholinesterase/chemistry , Azoles/pharmacology , X-Rays , Ethers , Molecular Docking Simulation , Alzheimer Disease/drug therapy , Structure-Activity RelationshipABSTRACT
Multidrug resistance and infectious disease have enormous spread despite drug discovery and development advancements. 1, 2, 4 -triazoles have been extensively studied, playing an imperative role in many pathologic conditions. A series of Schiff base triazoles; derived from Indole -3- acetic acid with substituted Benzaldehydes (5a-5g) were designed, synthesized, and evaluated through various Spectroanalytical techniques. SwissADME was used to assess physicochemical properties and pharmacokinetic drug-likeliness behavior. (5a-5g) were evaluated for their varied biological potential through antioxidant, antimicrobial, enzyme inhibition, and cytotoxic evaluation. Schiff bases express drug-like nature as they follow Lipinski's rule of five. 5b showed good antioxidant potential in total antioxidant capacity (TAC) and total reducing power (TRP) assays and was most active in the library in % free radical scavenging assay (%FRSA), showing 32% inhibition at 50 µg/mL concentration. Compounds showed antibacterial activity against various tested strains. 5e and 5f showed a minimum inhibitory concentration (MIC) value of 3.12 µg/mL for P.aeruginosa and K.pneumoniae, respectively. In the antifungal assay, only 5e inhibited one strain with a zone of inhibition >6 mm. These synthetic molecules possess good cytotoxic potential in the Brine Shrimp Lethality screening; 5c, 5d, and 5f exhibited LC50 =5.7 µg/mL. In the protein kinase inhibition assay, 5a, 5b, and 5g demonstrated inhibitory potential, showcasing the zone of inhibition as 7.5-10.5 mm for the bald one and 6-7.5 for the clear zone. These findings suggest that the compounds have antibacterial and cytotoxic potential, and there is a chance for further research and development in this area.
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2-Mercaptobenzothiazole and its derivatives are widely known for their diverse biological activities, particularly antimicrobial and anticancer potential. In the present study, a series of new hybrid compounds consisting of 2-mercaptobenzothiazole and different aryl amines 2(a-j) were synthesized and characterized by Fourier transform infrared (FTIR), 1H NMR, and 13C NMR spectral data. The synthesized compounds were screened for in vitro antibacterial activities through agar well diffusion assay. Among the series, 2b, 2c, and 2i exhibited significant antibacterial activity comparable to the standard drug levofloxacin. Based on their antibacterial potential, these compounds were further tested for their antibiofilm activity. All of the three compounds showed promising antibiofilm potential, even better than the standard drug cefadroxil at 100 µg/100 µL concentration. Molecular docking studies were performed to explore the antibacterial mechanism of these compounds. Strikingly, the molecule 2i shared the same hydrophobic pockets as those of levofloxacin in case of bacterial kinases and DNA gyrases. In addition, 2i exhibited satisfactory antibiofilm activity in comparison to the standard. Our study therefore suggested that the synthetic compound 2i possesses remarkable antibacterial activity and may serve as a lead molecule for the discovery of potent antibacterial agents.
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This study investigated the anti-arthritic potential of novel mannich-based derivatives of 2-mercaptobenzimidazole (AK7 and AK9) in rats. The compounds were characterized by NMR and FTIR spectroscopies and their acute anti-inflammatory effects were measured by carrageenan (CRG)-induced paw edema model. The most potent doses of AK7 and AK9 were subsequently evaluated in the complete Freund's adjuvant (CFA)-induced inflammatory arthritis model. AK7 and AK9 inhibited CRG-induced inflammation in a dose-dependent fashion and a similar reduction in CFA-induced paw inflammation was observed. Moreover, X-ray and histopathological analyses of AK7-treated animals displayed normal joint structure whereas AK9, despite of its anti-inflammatory effects, failed to protect against cartilage destruction. Interestingly, biochemical analysis revealed a better safety profile for AK7 than for AK9 and methotrexate. Both compounds suppressed mRNA levels of pro-inflammatory mediators (IRAK1, NF-κB1, TNF-α, IL1B) while only AK7 reduced the transcript levels of interstitial collagenase (MMP1). Molecular docking analysis of AK7 and AK9 with TNF-α and MMP1 also supported the experimental data. These findings clearly highlight the beneficial effects of AK7 in the prevention and/or treatment of inflammatory arthritis.
Subject(s)
Arthritis, Experimental , Arthritis , Animals , Rats , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Arthritis/chemically induced , Arthritis/drug therapy , Arthritis/pathology , Arthritis, Experimental/drug therapy , Arthritis, Experimental/pathology , Carrageenan , Cytokines , Inflammation/drug therapy , Matrix Metalloproteinase 1 , Molecular Docking Simulation , Plant Extracts/pharmacology , Rats, Wistar , Tumor Necrosis Factor-alpha/genetics , NF-kappa B/metabolismABSTRACT
Cancer is an uncontrolled, abnormal growth of cells and the second cause of death after cardiovascular disease. At present, chemotherapy and related drugs have three major categories. All three have characteristic action and toxicity levels of antitumor activity. Due to indications of unwanted side effects, the exploration of novel and selective anticancer agents is crucially required. Heterocyclic compounds have always played a major role in research for new drug discovery and development. 1,3,4-oxadiazole derivatives are heterocyclic isomers having pharmacological properties and play an important role as antiproliferative agents. The present review summarizes anticancer activities of 1,3,4-oxadiazole derivatives against different cell lines, such as HCT-116, MCF-7, HeLa, SMMC-7721, and A549. The results showed that 1,3,4-oxadiazole and its derivatives have the potential to play a major role as an anticancer agent with fewer side effects.
Subject(s)
Antineoplastic Agents , Cardiovascular Diseases , Humans , Antineoplastic Agents/pharmacology , Oxadiazoles/pharmacology , HeLa CellsABSTRACT
Objectives: The study was aimed at synthesis of the new derivatives of the pyrazolone nucleus, and their spectroscopic and pharmacological analysis and evaluation. Materials and Methods: Three series of compounds, with 2-picolinic acid (I a-d), 3-picolinic acid (II a-d), and 4-picolinic acid (III a-d) were synthesized and characterized by FT-IR, 1HNMR, 13C NMR, elemental, and melting points. The new compounds were then evaluated for their anti-oxidant, anti-inflammatory, and anti-epileptic potential. The hind paw edema model was used to screen anti-inflammatory potential, while the anticonvulsant effect was evaluated by employing the acute model of anti-epileptic activity. The in vivo anti-oxidant potential was determined through glutathione (GSH), glutathione-S-transferase (GST), catalase, and lipid peroxidase enzyme (LPO) assays. The expression of key biomarkers involved in inflammation and neuroprotection, including tumor necrotic factors alpha (TNF-α) and phosphorylated nuclear factor kappa B (NF-κB), was detected through enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Results: The tested compounds showed anti-oxidant potential. The selected compounds exhibited good anti-inflammatory potential. The PTZ-induced elevation of these inflammatory mediators and oxidative stress were ameliorated significantly by the selected compound Ic. Results of molecular analysis (ELISA and Western blot analysis) for potent compound Ic showed a prominent inhibitory effect against neuroinflammatory mediators, including TNF-α and NF-κB. Conclusion: It is concluded that the derivative Ic ameliorated PTZ-induced seizures, oxidative stress, and inflammatory cascades by regulating the NF-κB/ TNF-α/ROS pathway.
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Backgound: Alzheimer disease (AD) is a disastrous disease characterized by accretion of amyloid-beta plaques, neurofibrillary tangles inducing oxidative stress, loss of neuronal functions and continuous progression of cognitive impairment leading to severe dementia.Material and Methods: The newly synthesized benzimidazole derivative 4-chloro-3-(2-phenyl-1H-benzimidazole-1-sulfonyl) benzoic acid (CB) was evaluated for its anti-Alzheimer activity using in silico, in vivo, in vitro and molecular techniques (ELISA, WB & IHC).Results: In-silico studies revealed that CB has atomic contact energy values of -3.9 to -8.9 kcal/mol against selected targets. In vitro assay showed that CB caused acetylcholinesterase (AChE) and diphenyl-1-picrylhydrazyl inhibition. In-vivo findings revealed improvement in dementia as observed in the morris water maze test and Ymaze test. Amyloid-beta disaggregation, increased level of anti-oxidants, decreased expressions of inflammatory markers and enhanced cellular architecture were found in the cortex and hippocampus of treated rats in the histopathological examination, immunohistochemistry analysis, enzyme-linked immunosorbent assay and western blot analysis.Conclusions: This study revealed that CB possess different binding affinities with the Alzheimer-related targets and it possess anti-Alzheimer activity, mediated via AChE and amyloid-beta inhibition, anti-oxidant and anti-inflammatory pathways.
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Isoxazole derivatives are significant enough due to their wide range of pharmacological and therapeutic activities. The purpose of the current study is to use computational, in vitro, in vivo, and extensive molecular approaches to examine the possible anti-ulcer activity of 4-benzylidene-3 methyl-1,2-isoxazol-5(4H)-one (MBO). Biovia Discovery Studio visualizer (DSV) was utilized for virtual screening. A tissue antioxidant investigation, H+/K+-ATPase test, and anti-H. pylori activities were carried out. ELISA, immunohistochemistry, and PCR methods were employed for the proteome analysis. An ethanol-induced stomach ulcer model was used to examine the anti-ulcer potential in rats. The binding affinities for MBO ranged from -5.4 to -8.2 Kcal/mol. In vitro findings revealed inhibitory activity against H. pylori and the H+/K+-ATPase pump. It also enhanced levels of glutathione, catalase, and glutathione-S-transferase and reduced lipid peroxidation levels in gastric tissues of rats. In vivo results showed the gastro-protective effect of MBO (30 mg/kg) in ulcerative rat stomachs. The proteomic study revealed decreased expression of inflammatory markers (cyclooxygenase-2, p-NFkB, and TNF-α). In RT-PCR analysis, the expression levels of H+/K+-ATPase were reduced. Furthermore, ADMET (absorption, distribution, metabolism, excretion and toxicity) studies revealed that MBO has high GIT solubility and has a safer profile for cardiac toxicity. This study suggests that MBO displayed anti-ulcer potential, which may have been mediated through the inhibition of the H+/K+-ATPase pump, as well as antioxidant and anti-inflammatory pathways. It has the potential to be a lead molecule in the treatment of peptic ulcers with fewer adverse effects.
Subject(s)
Anti-Ulcer Agents , Helicobacter pylori , Stomach Ulcer , Animals , Anti-Ulcer Agents/chemistry , Antioxidants/metabolism , Ethanol/metabolism , Gastric Mucosa , Glutathione/metabolism , H(+)-K(+)-Exchanging ATPase/metabolism , Isoxazoles/pharmacology , Oxidative Stress , Plant Extracts/chemistry , Proteomics , Rats , Stomach Ulcer/chemically induced , Stomach Ulcer/drug therapy , Stomach Ulcer/prevention & controlABSTRACT
The present study aims to investigate the newly synthesized organotin (IV) complex (2E, 2'E) dibutylstannanediyl bis (4-(4-nitrophenyl) amino)-4-oxobut-2-enoate (DTN) for its anti-ulcer potential. Characterization performed by carbon nuclear magnetic resonance spectroscopy proved that all values are in the expected ranges of the new compound. Gastroprotective activity of DTN was evaluated through in-silico, anti-H. pylori, in-vitro, in-vivo, and ex-vivo proteomic analysis. In-silico analysis shows that DTN possess stable binding with protein targets involved in gastric ulcer pathophysiology. DTN exhibited an inhibitory effect against 2,2-diphenyl-1-picrylhydrazyl, H. pylori and hydrogen potassium ATPase (H+/K+-ATPase). The antiulcer activity was performed using an ethanol-induced gastric ulcer model in rats. Anti-oxidant profile of DTN showed a significant increase in glutathione-S-transferase, glutathione and catalase levels whereas lipid peroxidation levels were reduced. Histopathological findings confirmed that DTN protected the gastric mucosa of rats. Inflammatory markers tumor necrosis factor-alpha, nuclear factor kappa B, cyclooxygenase-2, interleukin 6 and interleukin-1ß were reduced and prostaglandin-E2 restored expression of these cytokines in DTN pretreated animals when analyzed by using immunohistochemistry, enzyme-linked immunosorbent assay and western blot techniques. In real-time polymerase chain reaction technique, the expression of H+/K+-ATPase was downregulated in DTN pretreated group. DTN did not cause any mortality up to 400 mg/Kg. This study indicates that the newly synthesized compound DTN, possess stable binding against selected targets. DTN exhibits a gastro-protective effect, mediated via anti-H. pylori, H+/K+-ATPase inhibition, anti-oxidant and anti-inflammatory pathways, exploring its therapeutic potential in gastric ulcer management.
Subject(s)
Anti-Ulcer Agents , Helicobacter pylori , Stomach Ulcer , Animals , Anti-Ulcer Agents/pharmacology , Anti-Ulcer Agents/therapeutic use , Antioxidants/pharmacology , H(+)-K(+)-Exchanging ATPase/metabolism , Helicobacter pylori/metabolism , Proteomics , Proton Pump Inhibitors/pharmacology , Proton Pump Inhibitors/therapeutic use , Rats , Stomach Ulcer/chemically induced , Stomach Ulcer/drug therapy , Stomach Ulcer/pathologyABSTRACT
Introduction: Several studies revealed that alcohol utilization impairs memory in adults; however, the underlying mechanism is still unclear. The production of inflammatory markers and reactive oxygen species (ROS) plays a major role in neurodegeneration, which leads to memory impairment. Therefore, targeting neuroinflammation and oxidative distress could be a useful strategy for abrogating the hallmarks of ethanol-induced neurodegeneration. Moreover, several studies have demonstrated multiple biological activities of thiazolidine derivatives including neuroprotection. Methods: In the current study, we synthesized ten (10) new thiazolidine-4-carboxylic acid derivatives (P1-P10), characterized their synthetic properties using proton nuclear magnetic resonance (1H-NMR) and carbon-13 NMR, and further investigated the neuroprotective potential of these compounds in an ethanol-induced neuroinflammation model. Results: Our results suggested altered levels of antioxidant enzymes associated with an elevated level of tumor necrosis factor-alpha (TNF-α), nuclear factor-κB (p-NF-κB), pyrin domain-containing protein 3 (NLRP3), and cyclooxygenase-2 (COX-2) in ethanol-treated animals. Ethanol treatment also led to memory impairment in rats, as assessed by behavioral tests. To further support our notion, we performed molecular docking studies, and all synthetic compounds exhibited a good binding affinity with a fair bond formation with selected targets (NF-κB, TLR4, NLRP3, and COX-2). Discussion: Overall, our results revealed that these derivatives may be beneficial in reducing neuroinflammation by acting on different stages of inflammation. Moreover, P8 and P9 treatment attenuated the neuroinflammation, oxidative stress, and memory impairment caused by ethanol.
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The diverse pharmacological role of dihydropyrimidinone scaffold has made it to be an interesting drug target. Because of the high incidence and mortality rate of breast cancer, there is a dire need of discovering new pharmacotherapeutic agents in managing this disease. A series of twenty-two derivatives of 6-(chloromethyl)-4-(4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3a-3k) and ethyl 6-(chloromethyl)-4-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a-4k) synthesized in a previous study were evaluated for their anticancer potential against breast cancer cell line. Molecular docking studies were performed to analyze the binding mode and interaction pattern of these compounds against nine breast cancer target proteins. The in vitro cell proliferation assay was performed against the breast cancer cell line MCF-7. The structure activity relationship of these compounds was further studied using QSARINS. Among nine proteins, the docking analysis revealed efficient binding of compounds 4f, 4e, 3e, 4g, and 4h against all target proteins. The in vitro cytotoxic assay revealed significant anticancer activity of compound 4f having IC50 of 2.15 µM. The compounds 4e, 3e, 4g, and 4h also showed anticancer activities with IC50 of 2.401, 2.41, 2.47 and 2.33 µM, respectively. The standard tamoxifen showed IC50 1.88 µM. The 2D qualitative structure-activity relationship (QSAR) analysis was also carried out to identify potential breast cancer targets through QSARINS. The final QSAR equation revealed good predictivity and statistical validation R 2 and Q 2 values for the model obtained from QSARINS was 0.98 and 0.97, respectively. The active compounds showed very good anticancer activities, and the binding analysis has revealed stable hydrogen bonding of these compounds with the target proteins. Moreover, the QSAR analysis has predicted useful information on the structural requirement of these compounds as anticancer agents with the importance of topological and autocorrelated descriptors in effecting the cancer activities.
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A series of novel phenoxy pendant isatins PI1-12 have been synthesized in excellent yields by a simple nucleophilic substitution reaction involving isatins and 1-(2-bromoethoxy)-4-substituted benzenes, and characterized by their FT-IR, 1H NMR, 13C NMR and GC-MS data, and in the case of PI4 by its single crystal X-ray analysis. The solid-state structure of PI4 showed an intriguing and unique 1D-supramolecular chain-based self-assembled structure, the driving force of which is mainly the strong antiparallel πâ¯π stacking and {â¯H-C-C-F}2 dimer synthons. This compound not only highlights the potential of the isatin moiety in forming strong antiparallel πâ¯π stacking interactions but also provides a platform to have considerable insight into the nature, strength and directionality of much debated π-π and C-Hâ¯F-C interactions. The in vitro biological studies revealed that three phenoxy pendant isatins PI1, PI2 and PI4 are highly potent inhibitors of acetylcholinesterase enzyme with IC50 values of 0.52 ± 0.073 µg ml-1, 0.72 ± 0.012 µg ml-1 and 0.68 ± 0.011 µg ml-1, respectively, showing comparable activity to the standard drug, donepezil (IC50 = 0.73 ± 0.015 µg ml-1). A simple and efficient synthesis of phenoxy pendant isatins PI1-12 from inexpensive and commercially available starting materials, and their high potential of acetyl cholinesterase inhibition provide an attractive opportunity to find more effective medication for Alzheimer's disease (AD).