Aiming to find effective anti-inflammatory agents, two new series of phthalimide derivatives 4a-h and 7a-f were synthesized and evaluated as inhibitors of COX and 5-LOX enzymes. The structures of all of the new compounds were confirmed by different spectroscopic analyses. The compounds in this study were designed with the intention of being moderately selective COX-2 inhibitors to avoid the negative effects of both highly selective COX-2 and non-selective COX inhibitors. The results of the in vitro screening showed that compounds 4c and 7a are the most potent compounds on COX-2 isoenzyme with moderate selectivity indices lower than that of celecoxib but higher than meloxicam. The two compounds also demonstrated powerful 5-LOX inhibitory activity with IC50 values less than 1 µM which is comparable to that of the reference drug zileuton. In addition all of the compounds under investigation could inhibit the nitric oxide production in LPS-induced RAW 264.7 macrophages. Furthermore, compounds 4c and 7a caused a reduction of the inflammatory mediators PGE-2, IL-6 and TNF-α supporting their anti-inflammatory effect in macrophages. Finally, molecular docking studies as well molecular dynamic simulations were carried out to investigate the binding pattern of the most potent compounds into the active site of both COX-2 and 5-LOX. Consequently, the achieved findings of this study suggest that those novel phthalimide derivatives could be promising leads for further optimization and the development of new anti-inflammatory drugs. New phthalimide derivatives were synthesized as anti-inflammatory agents. Compound 4c inhibited both COX-2 and LOX enzymes and production of NO. Also, it decreased the levels of PGE-2, IL-6 and TNF-α.

The application of simulated research approaches for the discovery and development of novel compounds as promising cancer drug candidates have still garnered widespread attention as an important goal in medicinal chemistry. In such context, a novel derived series of modified glycosides based on an isoindole-1,2,3-triazole-1,4-disubstituted-aryl hybrid system were synthesized from the terminal acetylenic compound (prepared from propargylation of 2-(4-hydroxyphenyl)isoindoline-1,3-dione (1)) and different glycosyl azides via click-based strategy. Furthermore, the afforded acetylated Iso-idolinedione-N1-glycosyl-1,2,3-triazole products were diacetylated to give the derived glycosyl-triazoles with deacetylated hydroxyls. On the other hand, the C-glycosyl analogues were also prepared from the (azidoethoxy)phenyl)isoindoline-1,3-dione followed by deprotection process. The cytotoxicity behaviour of resulted isoindoline-dione based 1,2,3-triazole glycosides was investigated towards the human cancer cells: human breast (PC3), colorectal (HCT-116), and hepatic (HepG-2) lines. The influence of attachment of the sugar part on the cytotoxicity results was obvious and the type of the attached sugar moiety where the glycosyl-1,2,3-triazoles with the xylopyranosyl moiety (compounds 6, 9 and 16) and galactopyranosyl (compound 8) were the most active. The latter accounted for the specific effect of the type of the sugar moiety. Docking investigation into epidermal growth factor receptor (EGFR) indicated potential interacting binding behaviours and mechanisms of inhibition. Molecular dynamics investigation revealed the possibility of attaining a stable binding mode of the glycoside 8 into EGFR’s site as well as the structural integrity of the catalytic domain. The electronic structure, molecular orbitals, and electrostatic potential of compound 8 were analysed by Density functional theory (DFT) calculations. HOMO-LUMO analysis demonstrated the electron-donating and electron-accepting potency, supporting the anticancer potential and aligning with the docking and dynamics results.

AIMS:A novel series of 1H-benzo[b][1,4]diazepine derivatives bearing different substitutions at positions 2 and 4 was designed, synthesized, and tested as anticancer agents. MARTIALS AND METHODS:The reaction of chalcone derivatives 5a-h with o-phenylenediamine (OPDA) in ethanol and the presence of acetic acid as a catalyst afforded the targeted 1H-benzo[b][1,4]diazepine derivatives (6a-h). The structures of the newly synthesized compounds were confirmed via spectral data and elemental analyses. These compounds were tested as in vitro anti-cancer agents against MCF7, PC3 cancer cells and BJ normal cells. RESULTS:Compound 6h showed the best efficacy with IC50 of 29.1 and 50.7 µM on MCF7 and PC3, respectively, compared to the reference drug with IC50 of 32.36 and 47.96 µM, respectively. 6h was tested on the BJ to investigate its selectivity on the tested cancer cells, and the selectivity index of 6h was 2.25 and 1.30 on MCF7 and PC3, respectively. It is important to note that compound 6h has strong selectivity, especially on MCF7, and moderate selectivity on PC3, both being more than that found in the reference drug. Moreover, 6h was investigated for further studies to explore its mechanism of action using DNA fragmentation, DNA damage, and gene expression techniques.

Colorectal cancer (CRC) is a serious public health concern worldwide. Immune checkpoint inhibition medication is likely to remain a crucial part of CRC clinical management. This study aims to create new super paramagnetic iron oxide nano-carrier (SPION) that can effectively transport miRNA to specific CRC cell lines. In addition, evaluate the efficiency of this nano-formulation as a therapeutic candidate for CRC. Bioinformatics tools were used to select a promising tumor suppressor miRNA (mir-497-5p). Green route, using Fusarium oxyporium fungal species, manipulated for the synthesis of SPION@Ag@Cs nanocomposite as a carrier of miR-497-5p. That specifically targets the suppression of PD1/PDL1 and CTLA4pathways for colorectal therapy. UV/visible and FTIR spectroscopy, Zeta potential and MTT were used to confirm the allocation of the miR-497 on SPION@Ag@Cs and its cytotoxicity against CRC cell lines. Immunofluorescence was employed to confirm transfection of cells with miR-497@NPs, and the down- regulation of CTLA4 in HT29, and Caco2 cell lines. On the other hand, PDL1 showed a significant increase in colorectal cell lines (HT-29 and Caco-2) in response to mir497-5p@Nano treatment. The data suggest that the mir-497 -loaded SPION@Ag@Cs nano-formulation could be a good candidate for the suppression of CTLA4in CRC human cell lines. Consequently, the targeting miR-497/CTLA4 axis is a potential immunotherapy treatment strategy for CRC.

Spiroindolin-2-ones with phosphonate function 17a‒t (20 analogs, 96‒72% yield) were generated by microwave synthetic methodology using azomethine cycloaddition of the appropriate 3,5-bis(ylidene)-4-piperidone-1-phosphonate 14a‒g. Single crystal X-ray analysis of 17d confirmed the structure. Promising 2D-monolayer antiproliferation properties (MTT assay) were observed for some of the synthesized agents with no harm to normal (RPE1) cell line. Compound 17h (R = 4-ClC6H4, R′ = H; IC50 = 3.08 μM; 6.6- and 3.1-fold the standard drugs, 5-fluorouracil and sunitinib, respectively) is the most distinguished agent against colon/HCT116 cell line. Compound 17f (R = 4-FC6H4, R′ = Cl; IC50 = 5.252 μM; 3.2-fold the activity of sunitinib, the clinically approved standard drug) also has significant activity against pancreatic/PaCa2 cell line. 3D-multicellular spheroid (HCT116) testing was also performed. Notable VEGFR-2 inhibitory properties were evident for some of the synthesized analogs. Considerable activity against COX-1/-2 and TNF-α, relative to the established NSAIDs ibuprofen and indomethacin, was also detected. CAM testing evidenced the anti-VEGFR-2 observations and anti-angiogenic properties. Internal and external validated QSAR models explored the functions necessary for the antiproliferation potency. In conclusion, the designed spiroindolin-2-ones conjugated with phosphonate function can be useful for optimizing novel anti-cancer therapeutic agent(s) with anti-angiogenic (anti-VEGFR-2) mode of action after considering more needed advanced pharmacological studies.

This study aims to synthesize a novel series of nicotinonitriles incorporating pyrazole, oxadiazole, isoindoline, thiadiazole, and thiazolidinone moieties (compounds 4-11). The synthesis utilizes 2-((3-cyano-4-(4-fluorophenyl)-6-(naphthalen-2-yl)pyridin-2-yloxy)acetohydrazide (3) as a key starting material to enhance potential anticancer activity. The molecular structures of compounds 4-11 were elucidated using various spectroscopic techniques and elemental analysis. The synthesized compounds were screened for cytotoxic activity against human cancer cell lines, including MCF-7 (human Caucasian breast adenocarcinoma), MDA-MB-231 (breast ductal carcinoma), and PC-3 (prostate cancer), using an MTT assay with doxorubicin as a reference drug. Among the tested compounds, 4, 6b, and 7 exhibited the most promising cytotoxic activity, with IC50 values ranging from 22.5 to 91.3 µM. The safety profile of these compounds was further evaluated using noncancerous human skin fibroblast cells (BJ-1). Notably, 6b and 7 demonstrated high selectivity indices (SI > 3) against cancer cells, indicating preferential cytotoxicity, whereas compound 4 lacked selectivity. Docking studies, consistent with experimental data, further supported the potential anticancer properties of compounds 4, 6b, and 7. Given their significant inhibitory effects on cancer cell lines with minimal to no impact on normal cells, compounds 6b and 7 are strong candidates for further drug development as potential anticancer agents.

Five compounds were isolated from the aerial parts of Chamaerops humilis L. and characterized as tricin-7-rutinoside (1), tricin (2), dihydrotricin (3) diasteroisomer of tricin 4’-O(erythro-β-guaiacyl glyceryl) ether (salcolin A)(4a), tricin-4’-O-(threo-β-guaiacyl glyceryl) ether (salcolin B) (4b) and (-)-(5s, 6s)-5,6-dihydro-3,8,10-trihydroxy-5-(4-hydroxy-3-methoxyphenyl)-6-hydroxymethyl-2,4-dimethoxy 7H benzo [e] xanthen-7-one (5). Their structures were elucidated by comparing their spectral data with those reported in the literature. To the best of our knowledge, compounds (3-5) were reported here for the first time from Chamaerops humilis. The methanolic extract of Chamaerops humilis (CHME) and the five isolated compounds were studied for its anti-diabetic effect using in vitro α-glucosidase and α-amylase inhibitory assay that showed a significant activity. The toxicological study indicated that CHME was safe up to 5000 mg/kg bw. Two doses were selected for the in vivo study (800 and 1600 mg/kg bw) and orally administered to high fat diet/streptozotocin-induced diabetic rats for 10 consecutive days. The results revealed that the CHME improved the blood glucose levels in a dose dependent manner, the dose 1600 mg/kg showed the best results dependently along the period of the experiment. CHME and the five isolated compounds were evaluated in silico for their anti-diabetic effect. The anti-inflammatory effect of CHME (1600 mg/kg bw) was proved by significant downregulation of expression for interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-1 (MMP-1) genes. In conclusion, CHME and its constituents may be a potential hypoglycemic agent working through the anti-inflammatory and enzyme inhibitory pathways. The docking studies demonstrated that compounds Tricin7-rutinoside and Salcolin isomers had promising binding energies of -9.10 kcal/mol and -8.70 kcal/mol, respectively, against α-amylase. These binding energies were superior to that of acarbose, which had a binding energy of -7.60 kcal/mol. In addition, docking analysis provided promising results for the inhibition of α-glucosidase by Tricin7-rutinoside and Dihydrotricin with binding affinity -7.9 kcal/mol and -7.9 kcal/mol, respectively while the binding affinity of acarbose is -6.40 kcal/mol. Overall, the methanolic extract from Chamaerops humilis exhibited good in silico of α-amylase and α-glucosidase enzyme inhibition potential. These findings suggest that these compounds may have potential as anti-diabetic agents, with further research needed to verify their efficacy and safety.

The objective of this study is to investigate the chemical composition of the leaves of Terminalia myriocarpa and to evaluate their α-glucosidase inhibitory activity aiming to be used as a safe antidiabetic. Consequently, 10 compounds were isolated using column and preparative thin-layer chromatographic techniques and identified as alphitolic acid, isovitexin, flavogallonic acid, nigaichigoside F1, quercetin, quadranoside IV, rosamultin, 19α-hydroxyasiatic acid, asiatic acid, and arjunic acid. Structure elucidation was based on chemical (acid hydrolysis) and spectroscopic (UV, 1 H, and 13C-NMR) analyses and findings were confirmed through comparison with published data. The α-glucosidase inhibitory activity of the methanol extract fractions and compounds isolated therefrom was evaluated in-vitro alongside that of acarbose (positive control). Results revealed that quercetin and flavogallonic acid were significantly active with half-maximal inhibitory concentrations (IC50) equal to 7.5 ± 0.09 and 21.0 ± 1.4 µM, respectively. Furthermore, the interaction of lavogallonic acid with α-glucosidase enzyme was verified by docking experiment. Accordingly, quercetin and flavogallonic acid could be considered safer natural alternatives to the currently availableα-glucosidase inhibitors.

New sulfonamide-triazole-glycoside hybrids derivatives were designed, synthesised, and investigated for anticancer efficacy. The target glycosides’ cytotoxic activity was studied with a panel of human cancer cell lines. Sulfonamide-based derivatives, 4, 7 and 9 exhibited promising activity against HepG-2 and MCF-7 (IC50 = 8.39–16.90 μM against HepG-2 and 19.57–21.15 μM against MCF-7) comparing with doxorubicin (IC50 = 13.76 ± 0.45, 17.44 ± 0.46 μM against HepG-2 and MCF-7, rescpectively). To detect the probable action mechanism, the inhibitory activity of these targets was studied against VEGFR-2, carbonic anhydrase isoforms hCA IX and hCA XII. Compoumds 7 and 9 gave favorable potency (IC50 = 1.33, 0.38 μM against VEGFR-2, 66, 40 nM against hCA IX and 7.6, 3.2 nM against hCA XII, respectively), comparing with sorafenib and SLC-0111 (IC50 = 0.43 μM, 53 and 4.8 nM, respectively). Moreover, the docking simulation was assessed to supply better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes that was used for further modification in the anticancer field.

Abstract The current study reports new sulfonamide-triazole-glycoside hybrids' design, synthesis, and anticancer activity. The target glycosides' cytotoxic activity was studied with a panel of human cancer cell lines. Azido sulfonamide compound 4 exhibited moderate activity against A-549 and HCT-116 and excellent potency against HepG-2 and MCF-7. Replacement of the azido group with 1,2,3-triazole- glycoside hybrids in 6-13 afforded variable activities against tested cell lines ranging from weak to excellent ones in acetylated glycosides 6-9. On the other hand, hydroxylated glycosides 10-13, revealed weak cytotoxicity except N-cyclohexylbenzene derivatives 11, 13 expressing promising activity against HepG-2. In addition, the hydroxylated glycoside 13 gave moderate activity against MCF-7. To detect the probable action mechanism, the inhibitory activity of the promising sulfonamide-triazole-glycoside hybrids was studied against VEGFR-2, carbonic anhydrase isoforms hCA IX and hCA XII. Moreover, the docking evaluation was simulated to supply better rationalization and gain insight into the binding affinity between their targeted enzymes and the promising derivatives and used for further modification in the anticancer field.

The prevalence of breast cancer as a significant public health concern necessitates continued exploration of natural resources for novel anti-cancer agents is crucial. Material and methods: Anticancer activity of plant extracts on monolayer breast cancer cell line (MCF7) with lower levels of toxicity towards normal (RPE1) underwent further assessment using a three-dimensional model (3D). The extract's effects were investigated through multiple assays including apoptosis induction using quantifying cleaved cytokeratin-18 (CK18) and DNA fragmentation. Additionally, the expression of Bcl-2 and Bax was quantitative using real-time PCR. The median lethal dose (LD50) was determined by the acute oral toxicity, while biomarkers associated with tumorigenesis, metastasis, and cell death were quantified by ELISA. Results: Limoniastrum monopetalum and Bauhinia variegata exhibited the most potent antitumor efficacy among the investigated extracts. They demonstrated potent cytotoxicity against MCF7 with no significant effect on hTERT RPE-1, with an IC50 of 100 mu M. The extract demonstrated effectiveness in killing cancer cells within 3D tumorlike structures, induced apoptosis through caspase-3 activation and cleavage of cytokeratin-18, up-regulated the tumor suppressor p53, down-regulated the anti-apoptotic Bcl-2 gene, and caused DNA fragmentation. Acute oral toxicity studies in mice indicated low toxicity, and in a syngeneic mouse tumor model, the extract significantly inhibited tumor growth, suggesting its potential for further development. Conclusion: Limoniastrum monopetalum and Bauhinia variegata exhibited the most potent antitumor efficacy among the investigated extracts.

A series of fluorinated chalcones (3a-f) was synthesized and confirmed by several spectral tools. The cytotoxic effect of this series was tested against a panel of different cancer cell lines (MCF7, A549, HCT116, and PC3). MTT assay revealed that chalcone 3f has the potent cytotoxic activity against all tested cancer cell lines except A549 cells. Chalcone 3f showed the least cytotoxic activity against the normal epithelial cell line RPE-1 and the lowest IC50 at 10.96 mu M relative to the IC50 of doxorubicin at 12.8 mu M against the human breast cancer cell line MCF7. Molecular docking studies showed a good interaction of chalcone 3f with the active site of histone demethylase (PLU-1/JARID1B) and Carboxy-terminal binding protein1 (CtBP1) proteins. Mechanistically, chalcone 3f induced cell cycle arrest at G2/M phase and apoptosis assessed by flow cytometry, as well as DNA fragmentation in MCF7 cells. Chalcone 3f upregulated mRNA expression levels of the apoptotic genes BAX, p53, and Caspase-7, Caspase-8, and Caspase-9, whereas mRNA expression levels of the antiapoptotic gene Bcl2, metastasis-related gene matrix metalloproteinase 1 (MMP1), and the autophagic markers ATG5 and LC3B were downregulated as quantified by qPCR. This study shows a cytotoxic effect of chalcone 3f against cancer cells and emerges as a promising therapeutic drug against breast cancer.

Pyrido[2,3-d]pyrimidines and thiazolo based scaffold were reported to exhibit valuable anticancer activity and inhibit EGFR tyrosine kinase receptors wild and mutant types as well. So a new series of 6,8diaryl pyrido[2,3-d]thiazolo[3,2-a]pyrimidinones 2a-c was synthesized and their confirmed chemical structures were established through various spectral analyses including IR, HNMR, CNMR and mass spectroscopy. Anticancer evaluation was performed through screening for these compounds against MCF-7, PC-3, HCT-116 and A-549 cancerous cell lines at a dose of 100 in comparison with erlotinib. The antiproliferative activity revealed that compound 2a was excellent and approximately equipotent with the reference (IC50= 13.25 and 11.05 μM) which implicated that substitution at position 6 and 8 greatly affect the cytotoxic activity. Furthermore, the promising compound 2a was subjected to molecular docking analysis against EGFR and EGFR kinases to examine the binding mode and elucidate the mechanism of the promising cytotoxic activity. Finally compound 2a has been shown to be good candidate that deserve further investigation.

Three previously undescribed dibenzylbutane lignans, laxilignans A-C, together with fifteen known compounds were isolated and characterized from the leaves of Terminalia laxiflora Engl. The structures of laxilignans A-C were elucidated by extensive 1D and 2D NMR analyses, together with mass spectrometry. The inhibitory activity of the isolated compounds against alpha-glucosidase enzyme, obtained from Saccharomyces cerevisiae, was evaluated in comparison to acarbose (IC50 = 16.42 +/- 0.14 mu M). The results revealed that corilagin, chebulagic acid, laxilignan A, termilignan B, termitomenin C, arjunglucoside II, and laxilignan B possess alpha-glucosidase inhibitory potential, with IC50 values in the range of 1.61 +/- 0.05 - 403.5 +/- 29.5 mu M, respectively. The results of the molecular docking revealed that the two laxilignans A and B showed comparable binding affinities to those of acarbose with the binding sites of the human alpha-glucosidase enzyme. These findings suggest that dibenzylbutane lignans may act as promising lead compounds for the development of alpha-glucosidase inhibitors.

A new preparation route for high-luminescent blue-emission pepsin copper nanoclusters (Pep-CuNCs) is introduced in this work. The synthesized nanoclusters are based on a pepsin molecule, which is a stomach enzyme that works to digest proteins that exist in undigested food. Here, we have developed an eco-friendly technique through microwave-assisted fast synthesis. The resulting copper nanoclusters (CuNCs) exhibit significant selectivity towards Pb(II) ions. The pepsin molecule was utilized as a stabilizer and reducing agent in the production procedure of Pep-CuNCs. The characteristics of the resulting Pep-CuNCs were studied in terms of size, surface modification, and composition using various sophisticated techniques. The CuNCs responded to Pb(II) ions through the fluorescence quenching mechanism of the CuNCs' fluorescence. Thus, great selectivity of Pep-CuNCs towards Pb(II) ions was observed, allowing sensitive determination of this metal ion at lab-scale and in the environment. The CuNCs have detection limits for Pb(II) in very tenuous concentration at a nanomalar scale (11.54 nM). The resulting Pep-CuNCs were utilized significantly to detect Pb(II) ions in environmental samples. Additionally, the activity of Pep-CuNCs on different human tumor cell lines was investigated. The data for the observed behavior indicate that the Pep-CuNCs displayed their activity against cancer cells in a dose dependent manner against most utilized cancer cell lines.

Alibrary of novel spiro[pyrazole-4,5′-isoxazoline]-5-one derivatives were designed and synthesized using a concise and efficient one-pot reaction protocol through 1,3-dipolar cycloaddition between 4-benzylidene-3-methyl-1-phenyl-1 H -pyrazol-5(4 H )-one and chlorooximes. The synthesized derivatives were elucidated and characterized based on their spectroscopic data, including infrared spectrometry(IR), 1 H NMR, 13 C NMR, and elemental and mass spectral analysis. The synthesized compounds were evaluated for their antitumor inhibition potency against four human cancer cell lines, including human prostatic adenocarcinoma (PC3), human colorectal carcinoma(HCT116), human liver hepatocellular carcinoma(HepG2) and breast adenocarcinoma (MCF7). The outcomes were compared with the standard reference drug Doxorubicin. Among the synthesized chlorooximes, compounds 6 d and 6 e were the most active compounds on all cell lines. The spiro[pyrazole-4,5′-isoxazoline]-5-one derivatives 7 a and 7 c were active on the HepG2 liver cancer cell line. In comparison, compounds 7 f and 7 g were moderately active on the MCF7 cell line. The structure-activity relationship was explored for the synthesized compounds. Besides, in silico analysis of physicochemical, adsorption, distribution, metabolism, excretion and toxicity(ADMET) properties were done to determine the potential capacity of drug candidates. Molecular docking study onto the epidermal growth factor(EGF) tyrosine kinase receptor(3POZ) was done for the most active compounds to validate the reliability of in vitro anticancer screenings.

A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 μM. The highest active derivatives (8a, 8 b, 8d, 9a, and 12b) were selected for IC50 screening. Compounds 8a, 8 b, and 9a showed the highest cytotoxic activities and were further investigated for wild EGFRWT and mutant EGFRT790M inhibitory activities. Compound 8a showed the highest inhibitory activities against EGFRWT and EGFRT790M with IC50 values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound 8a induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFRWT and EGFRT790M.

This work evaluates the toxicity of trimethyl chitosan (TMC), which prevents its use as an antiproliferative active compound. We report our trial to enhance its safe application by chelating with various amino acids (phenylalanine, glycine and lysine). The safety evaluation was achieved by studying the behavior of TMC–amino acid chelates against two normal human cell lines (BJ1 and RPE1), in comparison with a negative control and doxrobicin (positive control) standard samples. The results obtained show that phenylalanine and lysine play an effective role in enhancing the safety of TMC against normal cell lines, together with providing high thermal stability. Phenylalanine is superior in synthesized anticancer agents. It had IC 50 values against colon HCT116 and breast cancer MCF‐7cancer cell lines of 68.7 and 51.4 μg mL –1 This compound is more acceptable than the previous reported rutin flavonoid as an anticancer agent against HCT116 cell lines. © 2021 Society of Chemical Industry and John Wiley & Sons, Ltd

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2′-pyrrolidine-3′,3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a ‒ h . X-ray diffraction studies ( 6b‒d , h ) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.

Abstract A series of 1''-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3''-piperidine]-2,4''-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.