Fenamates and ibuprofen as foundational components in the synthesis of innovative, targeted COX-2 anti-inflammatory drugs, undergoing thorough biopharmacological assessments and in-silico computational studies.

Cyclooxygenase-2 plays a vital role in inflammation by catalyzing arachidonic acid conversion toward prostaglandins, making it a prime therapeutic objective. Selective COX-2 inhibitors represent significant progress in anti-inflammatory therapy, offering improved efficacy and fewer side effects. This study describes the synthesis of novel anti-inflammatory compounds from established pharmaceutically marketed agents like fenamates III-V and ibuprofen VI. Through rigorous in vitro testing, compounds 7b-c, and 12a-b demonstrated substantial in vitro selective inhibition, with IC50 values of 0.07 to 0.09 µM, indicating potent pharmacological activity. In vivo assessment, particularly focusing on compound 7c, revealed significant anti-inflammatory effects. Markedly, it demonstrated the highest inhibition of paw thickness (58.62 %) at the 5-hr mark compared to the carrageenan group, indicating its potency in mitigating inflammation. Furthermore, it exhibited a rapid onset of action, with a 54.88 % inhibition observed at the 1-hr mark. Subsequent comprehensive evaluations encompassing analgesic efficacy, histological characteristics, and toxicological properties indicated that compound 7c did not induce gastric ulcers, in contrast to the ulcerogenic tendency associated with mefenamic acid. Moreover, compound 7c underwent additional investigations through in silico methodologies such as molecular modelling, field alignment, and density functional theory. These analyses underscored the therapeutic potential and safety profile of this novel compound, warranting further exploration and development in the realm of pharmaceutical research.

Development of new LSM-83177 analogues as anti-tumor agents against colorectal cancer targeting p53-MDM2 interaction.

LSM-83177, a phenoxy acetic acid derivative, is a small molecule reported for its promising anti-tumor properties. Via inhibiting the interaction between MDM2 and p53, LSM-83177 can elevate the active p53 levels within cells, thereby promoting apoptosis and inhibiting tumor growth. Also, LSM-83177 has been shown to inhibit GST activity in colorectal cancer HT29 cells. In the current work, novel LSM-83177 hydrazone analogs 5a-f, 7a-b, 10a-e, and 13a-b have been designed according to the structure features of LSM-83177 and their binding mode in the active site of MDM2. The anti-cancer activity of the newly synthesized analogs is evaluated against the HT29 cell line. The most potent compounds, 7a and 10a, showed IC50 = 12.48 and 10.44 µg/ml, respectively, when compared with Cisplatin (IC50 = 11.32 µg/ml) as a reference drug. Compounds 7a and 10a were introduced for further inspection for p53-MDM2 protein-protein interaction, where they displayed IC50 values of 3.65 and 11.08 µg/ml, respectively. Furthermore, hydrazones 7a and 10a increased the p-53 expression levels by 3.22- and 4.25-fold, respectively; in addition, they effectively reduced the GST expression levels in HT29 cancer cells with 0.56- and 0.30-fold increments in comparison to the untreated control.

Novel imidazo[2,1-b]thiazoles and imidazo[1,2-a]pyridines tethered with indolinone motif as VEGFR-2 inhibitors and apoptotic inducers: Design, synthesis and biological evaluations.

The current study investigates the anticancer and VEGFR-2 inhibitory activities of 16 novel indolinone-grafted imidazo[2,1-b]thiazole and imidazo[1,2-a]pyridine derivatives (6a-h and 10a-h). The structures of these target compounds were confirmed using elemental and spectral analyses. All compounds were evaluated for their VEGFR-2 inhibitory activity in vitro, with eight compounds demonstrating promising results, exhibiting IC50 values in the sub-micromolar range (0.22 µM - 0.95 µM). Additionally, the anticancer potential of these compounds was assessed using an MTT assay against two breast cancer cell lines, MCF-7 and MDA-MB-231. Compounds 6a, 6f, 6 h, and 10f showed superior performance (IC50 = 9.79, 8.78, 8.35, and 10.88 µM, respectively) compared to the reference drug cisplatin (IC50 = 11.50 µM) against MDA-MB-231 cells. Based on their consistent VEGFR-2 inhibitory activity, compounds 6a, 6 h, and 10f were selected for further analysis. Molecular docking studies with VEGFR-2 (PDB ID: 4AGD) revealed binding behaviors similar to the co-crystallized ligand sunitinib. Among the reported target molecules, compound 10f exhibited the most desirable characteristics in terms of efficacy and safety and was further analyzed using density-functional theory (DFT) simulations to better understand its physical properties.

Discovery of novel quinolin-2-one derivatives as potential GSK-3ß inhibitors for treatment of Alzheimer's disease: Pharmacophore-based design, preliminary SAR, in vitro and in vivo biological evaluation.

Recently, glycogen synthase kinase-3ß (GSK-3ß) has been considered as a critical factor implicated in Alzheimer's disease (AD). In a previous work, a 3D pharmacophore model for GSK-3ß inhibitors was created and the results suggested that derivative ZINC67773573, VIII, may provide a promising lead for developing novel GSK-3ß inhibitors for the AD's treatment. Consequently, in this work, novel series of quinolin-2-one derivatives were synthesized and assessed for their GSK-3ß inhibitory properties. In vitro screening identified three compounds: 7c, 7e and 7f as promising GSK-3ß inhibitors. Compounds 7c, 7e and 7f were found to exhibit superior inhibitory effect on GSK-3ß with IC50 value ranges between 4.68 ± 0.59 to 8.27 ± 0.60 nM compared to that of staurosporine (IC50 = 6.12 ± 0.74 nM). Considerably, compounds 7c, 7e and 7f effectively lowered tau hyperphosphorylated aggregates and proving their safety towards the SH-SY5Y and THLE2 normal cell lines. The most promising compound 7c alleviated cognitive impairments in the scopolamine-induced model in mice. Compound 7c's activity profile, while not highly selective, may provide a starting point and valuable insights into the design of multi-target inhibitors. According to the ADME prediction results, compounds 7c, 7e and 7f followed Lipinski's rule of five and could almost permeate through the BBB. Molecular docking simulations showed that these compounds are well accommodated in the ATP binding site interacting by its quinoline-2-one ring through hydrogen bonding with the key amino acids Asp133 and Val135 at the hinge region. The findings of this study suggested that these new compounds may have potential as anti-AD drugs targeting GSK-3ß.

Identification of indole-grafted pyrazolopyrimidine and pyrazolopyridine derivatives as new anti-cancer agents: Synthesis, biological assessments, and molecular modeling insights.

In the current medical era, developing new PIM-1 inhibitors stands as a significant approach to cancer management due to the pivotal role of PIM-1 kinase in promoting cell survival, proliferation, and drug resistance in various cancers. This study involved designing and synthesizing new derivatives of pyrazolo[1,5-a]pyrimidines (6a-i) and pyrazolo[3,4-b]pyridines (10a-i) as potential anti-cancer agents targeting PIM-1 kinase. The cytotoxicity was screened on three cancer cell lines: A-549 (lung), PANC-1 (pancreatic), and A-431 (skin), alongside MRC5 normal lung cells to assess selectivity. Several pyrazolo[1,5-a]pyrimidines (6b, 6c, 6g, 6h, and 6i) and pyrazolo[3,4-b]pyridine (10f) demonstrated notable anticancer properties, particularly against A-549 lung cancer cells (IC50 range: 1.28-3.52 µM), also they exhibited significantly lower toxicity towards MRC5 normal cells. Thereafter, the compounds were evaluated for their inhibitory activity against PIM-1 kinase. Notably, 10f, bearing a 4-methoxyphenyl moiety, demonstrated good inhibition of PIM-1 with an IC50 of 0.18 µM. Additionally, 10f induced apoptosis and arrested cell cycle progression in A-549 cells. Molecular docking and dynamics simulations provided insights into the binding interactions and compounds' stability with PIM-1 kinase. The results highlight these compounds, especially 10f, as promising selective anticancer agents targeting PIM-1 kinase.

Mitigating the resistance of MCF-7 cancer cells to Doxorubicin under hypoxic conditions with novel coumarin based carbonic anhydrase IX and XII inhibitors.

In the present study, the design and synthesis of novel coumarin derivatives 8a-h, 11a-d and 16a-c as potential selective inhibitors for the tumor associated human carbonic anhydrase isoforms (hCA IX and XII) was reported. All the newly synthesized derivatives showed potent to mild activity against the targeted CA IX (KI = 0.08-9.57 µM), with selectivity indices over CA I (SI = 2.0-21.9) and over CA II (SI = 1.1-15.7). They showed similar activities against CA XII (KI = 0.06-9.48 µM) with selectivity indices over CA I (SI = 1.4-21.2) and CA II (SI = 0.9-15.5). Compound 16b featuring sulfonamide function possessed promising inhibitory activities against the targeted isoforms CA IX and XII with KI values of 0.08 and 0.06 µM, respectively. Interestingly, it was found that using compound 16b at a nontoxic concentration as an adjuvant with Doxorubicin against MCF-7 cells enhanced the cytotoxicity under hypoxia by almost 3.5 folds; IC50 decreased from 25.74 to 7.43 µM. Therefore, compound 16b restored the cytotoxicity of Doxorubicin against MCF-7 cells under hypoxia, almost as normoxia. Furthermore, flow cytometry analysis of a combination treatment of compound 16b and Doxorubicin to the MCF7 cell line revealed an increase in cell cycle arrest at the G2/M phase and a more efficient apoptotic effect than Doxorubicin alone. Furthermore, compound 16b showed no cytotoxicity against normal breast MCF-10A cell line (IC50 = 296.25 µM).

Novel anti-inflammatory agents featuring phenoxy acetic acid moiety as a pharmacophore for selective COX-2 inhibitors: Synthesis, biological evaluation, histopathological examination and molecular modeling investigation.

Inflammation management presents a critical challenge in modern medicine, with nonsteroidal anti-inflammatory drugs (NSAIDs) being a widely used therapeutic option. However, their efficacy is often accompanied by significant gastrointestinal adverse effects, necessitating the exploration of safer alternatives, particularly through the investigation of cyclooxygenase-2 (COX-2) inhibitors. This study endeavors to address this imperative through the synthesis and evaluation of pyrazoline-phenoxyacetic acid derivatives. Among the synthesized compounds, 6a and 6c emerged as promising candidates, demonstrating potent COX-2 inhibition with IC50 values of 0.03 µM for both and selectivity index = 365.4 and 196.9, respectively. Furthermore, these compounds exhibited efficacy in mitigating formalin-induced edema in male Wistar rats, accompanied by favorable safety profiles upon histological examination of vital organs. Comprehensive safety assessments, including evaluation of creatinine, AST, and ALT enzymatic as well as troponin T and creatine kinase-MB levels, further reinforce the promising attributes of the synthetic candidates. Molecular docking studies endorsed by molecular dynamic simulations corroborate the biological findings, elucidating significant protein-ligand interactions at COX-2 active sites indicative of therapeutic potential.

Unveiling the potential of isatin-grafted phenyl-1,2,3-triazole derivatives as dual VEGFR-2/STAT-3 inhibitors: Design, synthesis and biological assessments.

The use of VEGFR-2 inhibitors as a stand-alone treatment has proven to be ineffective in clinical trials due to the robustness of cellular response loops that lead to treatment resistance when only targeting VEGFR-2. The over-activation of the signal transducer/activator of transcription 3 (STAT-3) is expected to significantly impact treatment failure and resistance to VEGFR-2 inhibitors. In this study, we propose the concept of combined inhibition of VEGFR-2 and STAT-3 to combat induced STAT-3-mediated resistance to VEGFR-2 inhibition therapy. To explore this, we synthesized new isatin-grafted phenyl-1,2,3-triazole derivatives "6a-n" and "9a-f". Screening on PANC1 and PC3 cancer cell lines revealed that compounds 6b, 6 k, 9c, and 9f exhibited sub-micromolar ranges. The most promising molecules, 6b, 6 k, 9c, and 9f, demonstrated the highest inhibition when tested as dual inhibitors on VEGFR-2 (with IC50 range 53-82 nM, respectively) and STAT-3 (with IC50 range 5.63-10.25 nM). In particular, triazole 9f showed the best results towards both targets. Inspired by these findings, we investigated whether 9f has the ability to trigger apoptosis in prostate cancer PC3 cells via the assessment of the expression levels of the apoptotic markers Caspase-8, Bcl-2, Bax, and Caspase-9. Treatment of the PC3 cells with compound 9f significantly inhibited the protein expression levels of VEGFR-2 and STAT-3 kinases compared to the control.

Unveiling the anticancer potential of novel spirooxindole-tethered pyrazolopyridine derivatives.

In the current medical era, human health is confronted with various challenges, with cancer being a prominent concern. Therefore, enhancing the therapeutic arsenal for cancer with a constant influx of novel molecules that selectively target tumor cells while displaying minimal toxicity toward normal cells is imperative. This study delves into the antiproliferative and EGFR kinase inhibitory activities of newly reported spirooxindole-pyrazolo[3,4-b]pyridine derivatives 8a-h and 10a-h. The inhibitory effects on the growth of human cancer cell lines A-549 (lung carcinoma), Panc-1 (pancreatic carcinoma), and A-431 (skin epidermoid carcinoma) were evaluated, and the SAR has been clarified through analysis. With IC50 values in the single-digit micromolar range, compounds 8b, 8d, 10a-b, and 10d were shown to be the most effective antiproliferative candidates against the studied cancer cell lines. They also exerted negligible cytotoxicity (with selectivity scores between 8.63 and 30.02) against the human lung MRC5 cell line. Additionally, we investigated the potential inhibitory action of compounds 8b, 8d, 10a-b, and 10d on EGFR and VEGFR-2. 10a was this investigation's most effective EGFR inhibitor, with an IC50 value of 0.54 µM. Ultimately, the molecular docking analysis of congener 10a highlighted its effective suppression of EGFR by examining its binding mode and docking score compared to Erlotinib. These findings underscore the potential of spirooxindole-pyrazolo[3,4-b]pyridine derivatives as promising anticancer agents targeting EGFR kinase.

Design, synthesis, and biological evaluation of dinaciclib and CAN508 hybrids as CDK inhibitors.

The scaffolds of two known CDK inhibitors (CAN508 and dinaciclib) were the starting point for synthesizing two series of pyarazolo[1,5-a]pyrimidines to obtain potent inhibitors with proper selectivity. The study presented four promising compounds; 10d, 10e, 16a, and 16c based on cytotoxic studies. Compound 16a revealed superior activity in the preliminary anticancer screening with GI % = 79.02-99.13 against 15 cancer cell lines at 10 µM from NCI full panel 60 cancer cell lines and was then selected for further investigation. Furthermore, the four compounds revealed good safety profile toward the normal cell lines WI-38. These four compounds were subjected to CDK inhibitory activity against four different isoforms. All of them showed potent inhibition against CDK5/P25 and CDK9/CYCLINT. Compound 10d revealed the best activity against CDK5/P25 (IC50 = 0.063 µM) with proper selectivity index against CDK1 and CDK2. Compound 16c exhibited the highest inhibitory activity against CDK9/CYCLINT (IC50 = 0.074 µM) with good selectivity index against other isoforms. Finally, docking simulations were performed for compounds 10e and 16c accompanied by molecular dynamic simulations to understand their behavior in the active site of the two CDKs with respect to both CAN508 and dinaciclib.

Design, Synthesis, and Biological Evaluation of Novel Phenoxy Acetic Acid Derivatives as Selective COX-2 Inhibitors Coupled with Comprehensive Bio-Pharmacological Inquiry, Histopathological Profiling, and Toxicological Scrutiny.

COX-2 plays a key role in converting arachidonic acid into prostaglandins. This makes it a significant target for treating inflammation. Selective COX-2 inhibitors have marked a new phase in inflammatory treatment, providing significant effectiveness while reducing negative side effects. Herein, we aimed at the design and synthesis of new anti-inflammatory agents 5a-f, 7a-b, 10a-f, and 13a-b with expected selective inhibition for COX-2. Compounds 5d-f, 7b, and 10c-f showed significant COX-2 inhibition with IC50 in the range of 0.06-0.09 µM, indicating powerful pharmacological potential. In light of this, eight compounds were selected for further testing in vivo to assess their selectivity toward COX-1/COX-2 enzymes with the ability to reduce paw thickness. Compounds 5f and 7b showed significant anti-inflammatory effects without causing stomach ulcers, as they showed significant in vivo inhibition for paw thickness at 63.35% and 46.51%, as well as paw weight at 68.26% and 64.84%. Additionally, the tested compounds lowered TNF-α by 61.04% and 64.88%, as well as PGE-2 by 60.58% and 57.07%, respectively. Furthermore, these potent compounds were thoroughly analyzed for their pain-relieving effects, histological changes, and toxicological properties. Assessing renal and stomach function, as well as measuring liver enzymes AST and ALT, together with kidney indicators creatinine and urea, offered valuable information on their safety profiles. Molecular modeling studies explain the complex ways in which the strong interacts with the COX-2 enzyme. This comprehensive strategy emphasizes the therapeutic potential and safety profiling of these new analogues for managing inflammation.

Fragment merging approach for the design of thiazole/thiazolidine clubbed pyrazoline derivatives as anti-inflammatory agents: Synthesis, biopharmacological evaluation and molecular modeling studies.

Fragment merging approach was applied for the design of thiazole/thiazolidinone clubbed pyrazoline derivatives 5a-e, 6a-c, 7 and 10a-d as dual COX-2 and 5-LOX inhibitors. Compounds 5a, 6a, and 6b were the most potent and COX-2 selective inhibitors (IC50= 0.03-0.06 µM, SI = 282.7-472.9) with high activity against 5-LOX (IC50 = 4.36-4.86 µM), while compounds 5b and 10a were active and selective 5-LOX inhibitors with IC50 = 2.43 and 1.58 µM, respectively. In vivo assay and histopathological examination for most active candidate 6a revealed significant decrease in inflammation with higher safety profile in comparison to standard drugs. Compound 6a exhibited the same orientation and binding interactions as the reference COX-2 and 5-LOX inhibitors (celecoxib and quercetin, respectively). Consequently, compound 6a has been identified as a potential lead for further optimization and the development of safe and effective anti-inflammatory drugs.

Effect of hydrophobic extension of aryl enaminones and pyrazole-linked compounds combined with sulphonamide, sulfaguanidine, or carboxylic acid functionalities on carbonic anhydrase inhibitory potency and selectivity.

Design and synthesis of three novel series of aryl enaminones (3a-f and 5a-c) and pyrazole (4a-c) linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid functionalities were reported as carbonic anhydrase inhibitors (CAIs) using the "tail approach" strategy in their design to achieve the most variable amino acids in the middle/outer rims of the hCAs active site. The synthesised compounds were assessed in vitro for their inhibitory activity against the following human (h) isoforms, hCA I, II, IX, and XII using stopped-flow CO2 hydrase assay. Enaminone sulphonamide derivatives (3a-c) potently inhibited the target tumour-associated isoforms hCA IX and hCA XII (KIs 26.2-63.7 nM) and hence compounds 3a and 3c were further screened for their in vitro cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under normoxic and hypoxic conditions. Derivative 3c showed comparable potency against both MCF-7 and MDA-MB-231 cancer cell lines under both normoxic ((IC50 = 4.918 and 12.27 µM, respectively) and hypoxic (IC50 = 1.689 and 5.898 µM, respectively) conditions compared to the reference drug doxorubicin under normoxic (IC50 = 3.386 and 4.269 µM, respectively) and hypoxic conditions (IC50 = 1.368 and 2.62 µM, respectively). Cell cycle analysis and Annexin V-FITC and propidium iodide double staining methods were performed to reinforce the assumption that 3c may act as a cytotoxic agent through the induction of apoptosis in MCF-7 cancer cells.

WRH-2412 alleviates the progression of hepatocellular carcinoma through regulation of TGF-ß/ß-catenin/α-SMA pathway.

Hepatocellular carcinoma is considered one of the most lethal cancers, which is characterised by increasing prevalence associated with high level of invasion and metastasis. The novel synthetic pyrazolo[3,4-b]pyridine compound, WRH-2412, was reported to exhibit in vitro antitumor activity. This study was conducted to evaluate the antitumor activity of WRH-2412 in HCC induced in rats through affecting the TGF-ß/ß-catenin/α-SMA pathway. Antitumor activity of WRH-2412 was evaluated by calculating the rat's survival rate and by assessment of serum α-fetoprotein. Protein expression of TGF-ß, ß-catenin, E-cadherin, fascin and gene expression of SMAD4 and α-SMA were determined in hepatic tissue of rats. WRH-2412 produced antitumor activity by significantly increasing the rats' survival rate and decreasing serum α-fetoprotein. WRH-2412 significantly reduced an HCC-induced increase in hepatic TGF-ß, ß-catenin, SMAD4, fascin and α-SMA expression. In addition, WRH-2412 significantly increased hepatic E-cadherin expression.

Design, synthesis, in vitro, and in vivo evaluation of novel phthalazinone-based derivatives as promising acetylcholinesterase inhibitors for treatment of Alzheimer's disease.

Twenty novel phthalazinone-based compounds were designed as acetylcholinesterase (hAChE) inhibitors. Compounds 7e and 17c demonstrated comparable or superior activity compared to donepezil, respectively, in in vitro enzyme assay. Moreover, both compounds 7e and 17c possess minimal toxicity on hepatic and neuroblastoma cell lines. Besides, it was proved that compounds 7e and 17c have percentage alternations and a transfer latency time comparable to donepezil and can alleviate the cognitive impairment caused by the scopolamine-induced model in mice. The kinetic analysis for compound 17c suggested this compound as a mixed-type inhibitor that could bind to both the peripheral (PAS) and the catalytic site (CAS) of the hAChE enzyme. The synthesized molecules were subjected to in silico analyses, including molecular docking studies, and the outcomes were consistent with the in vitro findings.

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 toward hepatocellular carcinoma (HepG2) and breast cancer (MCF7) cell lines. The most active compounds on both cell lines were additionally evaluated for their in vitro CDK2 inhibitory 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.

New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study.

A new series of thiazolyl-pyrazoline derivatives (4a-d, 5a-d 6a, b, 7a-d, 8a, b, and 10a, b) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides (1a-b). These eighteen derivatives have been designed as anticipated EGFR/HER2 dual inhibitors. The efficacy of the developed compounds in inhibiting cell proliferation was assessed using the breast cancer MCF-7 cell line. Among the new synthesized thiazolyl-pyrazolines, compounds 6a, 6b, 10a, and 10b displayed potent anticancer activity toward MCF-7 with IC50 = 4.08, 5.64, 3.37, and 3.54 µM, respectively, when compared with lapatinib (IC50 = 5.88 µM). In addition, enzymatic assays were also run for the most cytotoxic compounds (6a and 6b) toward EGFR and HER2 to demonstrate their dual inhibitory activity. They revealed promising inhibition potency against EGFR with IC50 = 0.024, and 0.005 µM, respectively, whereas their IC50 = 0.047 and 0.022 µM toward HER2, respectively, compared with lapatinib (IC50 = 0.007 and 0.018 µM). Both compounds 6a and 10a induced apoptosis by arresting the cell cycle of the MCF-7 cell line at the G1 and G1/S phases, respectively. Molecular modeling studies for the promising candidates 6a and 10a showed that they formed the essential binding with the crucial amino acids for EGFR and HER2 inhibition, supporting the in vitro assay results. Furthermore, ADMET study predictions were carried out for the compounds in the study.

Insights into the effect of elaborating coumarin-based aryl enaminones with sulfonamide or carboxylic acid functionality on carbonic anhydrase inhibitory potency and selectivity.

Recently, different mechanisms for inhibition of carbonic anhydrases (CAs) have been reported, such as the classical zinc-binding (exerted by sulfonamides and carboxylic acids) as well as occluding the entrance of the CA active site (exerted by coumarins). In this manuscript, we studied the effect of combining the pharmacopheric parts responsible for these two mechanisms on CA inhibitory potency and selectivity through the design and synthesis of novel coumarins tethered with the zinc-binding sulfonamide (5a-f, 11a-b and 13a-b) or carboxylic acid (7a-f) groups. In addition, another set of coumarin derivatives (9a-b) with no zinc-binding group (ZBG) was designed to act as non-classical CA inhibitors. The synthesized coumarins were examined for their inhibitory activities towards four hCA isoforms I, II, IX and XII. Coumarin sulfonamides (5a-f, 11a-b and 13a-b) effectively inhibited both tumor-associated hCA IX (KIs: 8.9-133.5 nM) and hCA XII (KIs: 3.4-42.9 nM) isoforms, whereas coumarin carboxylic acids (7a-f) weakly affected hCA IX (KIs: 0.49-11.2 µM) and hCA XII (KIs: 0.51-10.1 µM) isoforms. The coumarin based inhibitors featuring zinc-binding sulfonamide or carboxylic acid group achieved low to moderate hCA IX/XII selectivity. Interestingly, the ZBG-free coumarin derivatives (9a-b) emerged not only as effective hCA IX (KIs = 93.3 and 63.8 nM, respectively) and hCA XII (KIs = 85.7 and 72.1 nM, respectively) inhibitors, but also as a highly hCA IX/XII selective inhibitors over the off-target hCA I/II isoforms (SIs > 1000). Coumarin 9a was further evaluated for its anti-proliferative effect on MCF-7 and PANC-1 cancer cell lines, as well as its effect on the cell cycle and apoptosis towards MCF-7 cell line.

New tilomisole-based benzimidazothiazole derivatives as anti-inflammatory agents: Synthesis, in vivo, in vitro evaluation, and in silico studies.

New tilomisole-based benzimidazothiazole derivatives were designed and synthesized in this work. Their anti-inflammatory activity was assessed through the in vivo carrageenan rat paw edema model, and the in vitro COX inhibition assay. Compounds 13, 20, 30, 40, 43, and 46 demonstrated values of inhibition of induced edema in the in vivo assay comparable to celecoxib. All the synthesized compounds expressed their activity on COX-2 enzyme more than COX-1, proving their advantageous selectivity. In addition, compounds 13, 16, 20, 25, and 46 displayed lower IC50 values than celecoxib as a reference drug against COX-2 enzyme; having values of 0.09, 13.87, 32.28, 33.01, and 5.18 nM respectively vs 40.00 nM for celecoxib. Particularly, the most active compound (13) with its extreme potency (400 folds more potent than celecoxib) exhibited a notable high selectivity index (SI = 159.5). In silico studies, including ADMET prediction, compliance to Lipinski's rule of five, and molecular docking into the active site of both COX isozymes were conducted for the synthesized compounds. The results suggested that these compounds are good candidates for orally active drugs, and docking revealed higher number of interactions with COX-2 for 13 as the most active compound compared with COX-1 reflecting its advantageous selectivity and explaining its extreme potency.

Identification of 3-(piperazinylmethyl)benzofuran derivatives as novel type II CDK2 inhibitors: design, synthesis, biological evaluation, and in silico insights.

In the current work, a hybridisation strategy was adopted between the privileged building blocks, benzofuran and piperazine, with the aim of designing novel CDK2 type II inhibitors. The hybrid structures were linked to different aromatic semicarbazide, thiosemicarbazide, or acylhydrazone tails to anchor the designed inhibitors onto the CDK2 kinase domain. The designed compounds showed promising CDK2 inhibitory activity. Compounds 9h, 11d, 11e and 13c showed potent inhibitory activity (IC50 of 40.91, 41.70, 46.88, and 52.63 nM, respectively) compared to staurosporine (IC50 of 56.76 nM). Moreover, benzofurans 9e, 9h, 11d, and 13b showed promising antiproliferative activities towards different cancer cell lines, and non-significant cytotoxicity on normal lung fibroblasts MRC-5 cell line. Furthermore, a cell cycle analysis as well as Annexin V-FITC apoptosis assay on Panc-1 cell line were performed. Molecular docking simulations were performed to explore the ability of target benzofurans to adopt the common binding pattern of CDK2 type II inhibitors.