Bile-Acid-Appended Triazolyl Aryl Ketones: Design,Synthesis, In Vitro Anticancer Activity and Pharmacokinetics in Rats

A library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as ¹H and ¹³C NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 µM against MCF-7 (human breast adenocarcinoma) and 4T1 (mouse mammary carcinoma) cells. In vitro cytotoxicity studies on the synthesized conjugates against MCF-7 and 4T1 cells indicated one of the conjugate 6cf to be most active against both cancer cell lines, with IC₅₀ values of 5.71 µM and 8.71 µM, respectively, as compared to the reference drug docetaxel, possessing IC₅₀ values of 9.46 µM and 13.85 µM, respectively. Interestingly, another compound 6af (IC₅₀ = 2.61 µM) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC₅₀ = 9.46 µM) against MCF-7. In addition, the potent compounds (6cf and 6af) were found to be non-toxic to normal human embryonic kidney cell line (HEK 293), as evident from their cell viability of greater than 86%. Compound 6cf induces higher apoptosis in comparison to 6af (46.09% vs. 33.89%) in MCF-7 cells, while similar apoptotic potential was observed for 6cf and 6af in 4T1 cells. The pharmacokinetics of 6cf in Wistar rats showed an MRT of 8.47 h with a half-life of 5.63 h. Clearly, these results suggest 6cf to be a potential candidate for the development of anticancer agents.     

Synthesis and Biological Evaluation of Amino Chalcone Derivatives as Antiproliferative Agents

Chalcone is a common scaffold found in many biologically active compounds. The chalcone scaffold was also frequently utilized to design novel anticancer agents with potent biological efficacy. Aiming to continue the research of effective chalcone derivatives to treat cancers with potent anticancer activity, fourteen amino chalcone derivatives were designed and synthesized. The antiproliferative activity of amino chalcone derivatives was studied in vitro and 5-Fu as a control group. Some of the compounds showed moderate to good activity against three human cancer cells (MGC-803, HCT-116 and MCF-7 cells) and compound 13e displayed the best antiproliferative activity against MGC-803 cells, HCT-116 cells and MCF-7 cells with IC₅₀ values of 1.52 μM (MGC-803), 1.83 μM (HCT-116) and 2.54 μM (MCF-7), respectively which was more potent than the positive control (5-Fu). Further mechanism studies were explored. The results of cell colony formatting assay suggested compound 10e inhibited the colony formation of MGC-803 cells. DAPI fluorescent staining and flow cytometry assay showed compound 13e induced MGC-803 cells apoptosis. Western blotting experiment indicated compound 13e induced cell apoptosis via the extrinsic/intrinsic apoptosis pathway in MGC-803 cells. Therefore, compound 13e might be a valuable lead compound as antiproliferative agents and amino chalcone derivatives worth further effort to improve amino chalcone derivatives’ potency.     

Design,Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives

Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions C₁ and C₄ on the A ring of sinomenine. Twenty-three compounds were synthesized and characterized by spectroscopy (IR, ¹H-NMR, ¹³C-NMR, and HRMS). They were further evaluated for their cytotoxic activity against five cancer cell lines, MCF-7, Hela, HepG2, SW480 and A549, and a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine-containing compounds exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, we searched for cancer-related core targets and verified their interaction with derivatives through molecular docking. The chlorine-containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were consistent with the cytotoxic results. Overall, results indicate that chlorine-containing derivatives might be a promising lead for the development of new anticancer agents.     

Pyrrolizine/Indolizine-NSAID Hybrids: Design,Synthesis, Biological Evaluation,and Molecular Docking Studies

In the current study, eight new hybrids of the NSAIDs, ibuprofen and ketoprofen with five pyrrolizine/indolizine derivatives were designed and synthesized. The chemical structures of these hybrids were confirmed by spectral and elemental analyses. The antiproliferative activities of these hybrids (5 μM) was investigated against MCF-7, A549, and HT-29 cancer cell lines using the cell viability assay, MTT assay. The results revealed 4–71% inhibition of the growth of the three cancer cell lines, where 8a,e,f were the most active. In addition, an investigation of the antiproliferative activity of 8a,e,f against MCF-7 cells revealed IC₅₀ values of 7.61, 1.07, and 3.16 μM, respectively. Cell cycle analysis of MCF-7 cells treated with the three hybrids at 5 μM revealed a pro-apoptotic increase in cells at preG1 and cell cycle arrest at the G1 and S phases. In addition, the three hybrids induced early apoptotic events in MCF-7 cells. The results of the molecular docking of the three hybrids into COX-1/2 revealed higher binding free energies than their parent compounds 5a,c and the co-crystallized ligands, ibuprofen and SC-558. The results also indicated higher binding free energies toward COX-2 over COX-1. Moreover, analysis of the binding modes of 8a,e,f into COX-2 revealed partial superposition with the co-crystallized ligand, SC-558 with the formation of essential hydrogen bonds, electrostatic, or hydrophobic interactions with the key amino acid His90 and Arg513. The new hybrids also showed drug-likeness scores in the range of 1.06–2.03 compared to ibuprofen (0.65) and ketoprofen (0.57). These results above indicated that compounds 8a,e,f deserve additional investigation as potential anticancer candidates.     

Histone Deacetylase Inhibitory Activity and Antiproliferative Potential of New [6]-Shogaol Derivatives

Twenty newly synthesized derivatives of [6]-shogaol (4) were tested for inhibitory activity against histone deacetylases. All derivatives showed moderate to good histone deacetylase inhibition at 100 µM with a slightly lower potency than the lead compound. Most potent inhibitors among the derivatives were the pyrazole products, 5j and 5k, and the Michael adduct with pyridine 4c and benzothiazole 4d, with IC₅₀ values of 51, 65, 61 and 60 µM, respectively. They were further evaluated for isoform selectivity via a molecular docking study. Compound 4d showed the best selectivity towards HDAC3, whereas compound 5k showed the best selectivity towards HDAC2. The potential derivatives were tested on five cancer cell lines, including human cervical cancer (HeLa), human colon cancer (HCT116), human breast adenocarcinoma cancer (MCF-7), and cholangiocarcinoma (KKU100 and KKU-M213B) cells with MTT-based assay. The most active histone deacetylase inhibitor 5j exhibited the best antiproliferative activity against HeLa, HCT116, and MCF-7, with IC₅₀ values of 8.09, 9.65 and 11.57 µM, respectively, and a selective binding to HDAC1 based on molecular docking experiments. The results suggest that these compounds can be putative candidates for the development of anticancer drugs via inhibiting HDACs.     

Amide derivatives of 4-azaindole: Design,synthesis, and EGFR targeting anticancer agents

Abstract

A series of amide derivatives of azaindole-oxazoles (11a-n) were designed and synthesized and their structures were confirmed by ¹HNMR, ¹³CNMR and mass spectral analysis. Further, these derivatives were screened for their anticancer activity against human cancer cell lines viz; MCF7 (breast), A549 (lung) and A375 (melanoma). In vitro anticancer activity screening indicated that most of the hybrids exhibited potent inhibitory activities in a variety of cancer cell lines. Among the compounds 11d, 11e, 11f, 11j, 11k, 11l, 11m, and 11n were exhibited more potent activity than standard, in those mainly two compounds 11m and 11j were exhibited excellent activity in MCF-7 cell line with IC₅₀ values 0.034 and 0.036?µM. Moreover, all these compounds were carried out their molecular docking studies on EGFR receptor results indicated that two potent compounds 11m and 11j were strongly binds to protein EGFR (PDB ID: 4hjo). It was found that the energy calculations were in good agreement with the observed IC₅₀ values.     

Stereoselective Synthesis of the Di-Spirooxindole Analogs Based Oxindole and Cyclohexanone Moieties as Potential Anticancer Agents

A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins 3a–f (isatin, 3a, 6-chloroisatin, 3b, 5-fluoroisatin, 3c, 5-nitroisatin, 3d, 5-methoxyisatin, 3e, and 5-methylisatin, 3f, and (2S)-octahydro-1H-indole-2-carboxylic acid 2, in situ azomethine ylides reacted with the cyclohexanone based-chalcone 1a–f to afford the target di-spirooxindole compounds 4a–n. This one-pot method provided diverse structurally complex molecules, with biologically relevant spirocycles in a good yields. All synthesized di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were evaluated for their anticancer activity against four cancer cell lines, including prostate PC3, cervical HeLa, and breast (MCF-7, and MDA-MB231) cancer cell lines. The cytotoxicity of these di-spirooxindole analogs was also examined against human fibroblast BJ cell lines, and they appeared to be non-cytotoxic. Compound 4b was identified as the most active member of this series against prostate cancer cell line PC3 (IC₅₀ = 3.7 ± 1.0 µM). The cyclohexanone engrafted di-spirooxindole analogs 4a and 4l (IC₅₀ = 7.1 ± 0.2, and 7.2 ± 0.5 µM, respectively) were active against HeLa cancer cells, whereas NO₂ substituted isatin ring and meta-fluoro-substituted (2E,6E)-2,6-dibenzylidenecyclohexanone containing 4i (IC₅₀ = 7.63 ± 0.08 µM) appeared to be a promising agent against the triple negative breast cancer MDA-MB231 cell line. To explore the plausible mechanism of anticancer activity of di-spirooxindole analogs, molecular docking studies were investigated which suggested that spirooxindole analogs potentially inhibit the activity of MDM2.     

Synthesis,cytotoxic assessment,and molecular docking studies of 2,6-diaryl-substituted pyridine and 3,4- dihydropyrimidine-2(1H)-one scaffolds

Cancer is one of the main global health problems. In order to develop novel antitumor agents, we synthesized 3,4-dihydropyrimidine-2(1H)-one (DHPM) and 2,6-diaryl-substituted pyridine derivatives as potential antitumor structures and evaluated their cytotoxic effects against several cancer cell lines. An easy and convenient method is reported for the synthesis of these derivatives, employing cobalt ferrite (CoFe ₂ O ₄ @SiO ₂ -SO ₃ H) magnetic nanoparticles under microwave irradiation and solvent-free conditions. The structural characteristics of the prepared nanocatalyst were investigated by FTIR, XRD, SEM, and TGA techniques. In vitro cytotoxic effects of the synthesized products were assessed against the human breast adenocarcinoma cell line (MCF-7), gastric adenocarcinoma (AGS), and human embryonic kidney (HEK293) cells via MTT assay. The results indicated that compound 4r (DHPM derivative) was the most toxic molecule against the MCF-7 cell line (IC ₅₀ of 0.17 μg/mL). Moreover, compounds 4j and 4r (DHPM derivatives) showed excellent cytotoxic activities against the AGS cell line, with an IC ₅₀ of 4.90 and 4.97 μg/mL, respectively. Although they are pyridine derivatives, compounds 5g and 5m were more active against the MCF-7 cell line. Results showed that the candidate compounds exhibited low cytotoxicity against HEK293 cells. The kinesin Eg5 inhibitory potential of the candidate compounds was evaluated by molecular docking. The docking results showed that, among the pyridine derivatives, compound 5m had the most free energy of binding (–9.52 kcal/mol) and lowest Ki (0.105 μM), and among the pyrimidine derivatives, compound 4r had the most free energy of binding (–7.67 kcal/mol) and lowest Ki (2.39 μM). Ligand-enzyme affinity maps showed that compounds 4r and 5m had the potential to interact with the Eg5 binding site via H-bond interactions to GLU116 and GLY117 residues. The results of our study strongly suggest that DHPM and pyridine derivatives inhibit important tumorigenic features of breast and gastric cancer cells. Our results may be helpful in the further design of DHPMs and pyridine derivatives as potential anticancer agents.     

Synthesis,Molecular Docking Studies and In Silico ADMET Screening of New Heterocycles Linked Thiazole Conjugates as Potent Anti-Hepatic Cancer Agents

Thiazoles are important scaffolds in organic chemistry. Biosynthesis of thiazoles is considered to be an excellent target for the design of novel classes of therapeutic agents. In this study, a new series of 2-ethylidenehydrazono-5-arylazothiazoles 5a–d and 2-ethylidenehydrazono-5-arylazo- thiazolones 8a–d were synthesized via the cyclocondensation reaction of the appropriate hydrazonyl halides 4a–d and 7a–d with ethylidene thiosemicarbazide 3, respectively. Furthermore, the thiosemicarbazide derivative 3 was reacted with different bromoacetyl compounds 10–12 to afford the respective thiazole derivatives 13–15. Chemical composition of the novel derivatives was established on bases of their spectral data (FTIR, ¹H-NMR, ¹³C-NMR and mass spectrometry) and microanalytical data. The newly synthesized derivatives were screened for their in vitro anti-hepatic cancer potency using an MTT assay. Moreover, an in silico technique was used to assess the interaction modes of the compounds with the active site of Rho6 protein. The docking studies of the target Rho6 with the newly synthesized fourteen compounds showed good docking scores with acceptable binding interactions. The presented results revealed that the newly synthesized compounds exhibited promising inhibition activity against hepatic cancer cell lines (HepG2).     

Synthesis and biological applications of some novel 8-Hydroxyquinoline urea and thiourea derivatives

A number of novel urea and thiourea derivatives of 8-hydroxyquinoline have been designed, synthesized and evaluated for their anticancer activities. The structures of the new compounds were established by spectroscopic techniques, ¹H NMR, ¹³C NMR, and mass spectrometry. The in vitro cytotoxicity against MCF7, and MDA-MB-231 cell lines were assessed by MTT assay. Six of the 11 compounds synthesized namely 5b, 5c, 5f, and 6b-d exhibited cytotoxicity with IC₅₀ values ranged between 0.5 and 42.4 µM. Apoptotic features of cells treated with 5b compound were observed via florescent microscopy using DAPI and ethidium bromide/acridine orange staining against MCF-7 cells. Molecular docking of these molecules against 16 potential breast cancer protein revealed that these compounds could interact with the active site of poly (ADP-ribose) polymerase-1 (PARP1), B-cell lymphoma-extra large (Bcl-xL) and PARP5A (Tankyrase 1) by forming hydrogen bonds, π-π interactions and hydrophobic interactions. The docked poses of these molecules were observed to be similar in the active site of each of these targets.     

Discovery of New S‐Glycosides and N‐Glycosides of Pyridine‐biphenyl System with Antiviral Activity and Induction of Apoptosis in MCF7 Cells

Glycosylation of small molecule‐based drugs can dramatically improve the biological activities of the parent scaffold. In the current study, S‐glycosides and N‐glycosides of polyfunctionalized pyridine‐biphenyl system tethered with benzotriazole moiety were designed and synthesized. S‐Glycosides of pyridine‐2‐thione derivatives 5a – h and N‐glycosides of pyridine‐2‐one derivatives 9a , b were synthesized by a facile, convenient, and high‐yielding procedure. The epimers glucose and galactose, acetylated or deacetylated, were used to form the glycone part. The structures of these compounds were confirmed by microanalysis and spectroscopic data (IR, ¹ H–NMR, and ¹³C‐NMR). The anticancer activities of the target compounds, in comparison with standard cisplatin, were assessed by MTT assay against MCF7 cell line. Compounds 4f , 4g , 5f , and 5h exhibited the highest cytotoxic effect on MCF7. The anticancer effect of these four compounds induced the apoptosis as evident by the up‐regulated expression of the apoptotic genes Bax and p53 and down‐regulated expression of the anti‐apoptotic gene BCl₂. S‐Glycoside derivatives are more active than N‐glycosides. Moreover, the nontoxic doses of the tested compounds were evaluated in MA104, FRHK4, BGM, Hep2, and Vero cells. Compounds 4a – d and 5a – d were also evaluated for their antiviral effect against HSV‐1, HAV, and rotavirus Wa strain. The compounds' results showed less, moderated, and high antiviral activities. The docking study for these compounds with MDM2 revealed that deacetylated galactose is important for binding with the receptor as it facilitates the formation of hydrogen bond in the receptor. Rapid overlay of chemical structures analysis was employed to understand the compounds' similarity on the basis of their shape structure using the Tanimoto scores.     

Design,synthesis, anticancer activity,and in silico studies of novel imidazo[1,2-a]pyridine based 1H-1,2,3-triazole derivatives

A novel series of imidazo[1,2-a]pyridine based 1H-1,2,3-triazole derivatives were designed, synthesized, and evaluated for their anticancer activity against two different human cancer cell lines. Most of the synthesized compounds displayed anticancer activity with IC₅₀ values from 2.35 to 120.46 μM. Furthermore, compounds 9b , 9c, 9d, 9f , and 9j showed potent inhibitory activity against cancer cell lines, with IC₅₀ values close to that of standard drug. It is important to note that compound 9d was more potent than the standard drug cisplatin with IC₅₀ values of 10.89 and 2.35 μM against Hela cell line and MCF-7 cell line, respectively.     

Synthesis,pharmacological evaluation,and molecular modeling studies of novel isatin hybrids as potential anticancer agents

A novel series of isatin hybrids 5a-g was designed, synthesized, and characterized spectroscopically. The synthesized compounds were evaluated for their cytotoxic activity against the human breast cancer cell line (MCF-7) by in vitro MTT assay. Amongst the tested compounds, 5e compound bearing benzyl moiety at N₄ piperazine was found to be the most active with the promising IC₅₀ (12.47 µM). Moreover, the active compounds 5e and 5g were subjected to antitumor evaluation (in vivo) against Dalton’s ascitic lymphoma (DAL) cell line and the results suggested that the best active compound 5e can normalize the blood picture in comparison to the standard drug. An in silico molecular docking study using the crystal structure of Hsp90 protein described the role of significant protein–ligand interactions and revealed more insights into the binding mode. The drug-likeliness of the compounds was predicted based on Lipinski's rule of five and pharmacokinetic ADME parameters. Hence, the synthesized isatin hybrids could be novel starting point anticancer lead compounds demonstrating drug-like properties which can be explored further for anticancer drug discovery.     

5-Aryl-1-Arylideneamino-1H-Imidazole-2(3H)-Thiones: Synthesis and In Vitro Anticancer Evaluation

A novel series of N-1 arylidene amino imidazole-2-thiones were synthesized, identified using IR, ¹H-NMR, and ¹³C-NMR spectral data. Cytotoxic effect of the prepared compounds was carried out utilizing three cancer cell lines; MCF-7 breast cancer, HepG2 liver cancer, and HCT-116 colon cancer cell lines. Imidazole derivative 5 was the most potent of all against three cell lines. DNA flow cytometric analysis showed that, imidazoles 4d and 5 exhibit pre-G1 apoptosis and cell cycle arrest at G2/M phase. The results of the VEGFR-2 and B-Raf kinase inhibition assay revealed that compounds 4d and 5 displayed good inhibitory activity compared with reference drug erlotinib.     

Synthesis,biological evaluation and molecular docking study of dihydropyrimidine derivatives as potential anticancer agents

A series of dihydropyrimidine analogues were prepared via one-pot Biginelli three-component condensation reaction and characterized by NMR, FT-IR, MS spectra, and element analysis. Subsequently, they were screened for in vitro anticancer effect. These analogues revealed good cytotoxic activity against three human cancer cell lines including MCF-7, HepG-2, and A549. Among these analogues, compounds 4d and 4h were the most potent against three cell lines. Cell viability assays indicated 4a and 4c had lower cytotoxicity. In vitro cytotoxicity study on all synthesized compounds demonstrated that introduction of electron withdrawing substituents on C4 position of phenyl ring of dihydropyrimidine contributed to the antiproliferative potency. Moreover, in silico molecular docking results stipulated a sign of good correlation between experimental activity and calculated binding affinity. It proved 4d and 4h as the strongest compounds. Binding modes of analogues proposed the involvement of hydrophobic interactions and hydrogen bonds with Eg5 active site. Structure activity relationship studies indicated that incorporating electron withdrawing substituents on C4 position of phenyl ring of dihydropyrimidine are important for this biological activity.     

Synthesis,in vitro biological evaluation and in silico docking studies of new quinazolin-2,4-dione analogues as possible anticarcinoma agents

Today, cancer is considered as one of the major reasons of death in human beings worldwide. We reported herein the synthesis, anticancer activity, and in silico docking studies of a series of nine quinazolindione-based scaffolds bearing pyrimidine, pyridine, pyran, and pyrazole moieties ( 1 - 9 ) through Michael addition, Vilsmeier-Haack, Claisen-Schmidt, and nucleophilic addition reactions. The chemical structures of the newly prepared compounds were ascertained by means of their spectral analysis techniques like IR, ¹H-nuclear magnetic resonance (NMR), ¹³C-NMR, mass spectroscopy, and elemental analysis. This work was conducted to investigate the implication of Rho7 protein in breast and hepatocellular cancer cells aggressively. MCF-7 and HepG2 cells have been selected as models for the effect of protein expression on breast and hepatocellular cancers cell growth. All prepared compounds were biologically evaluated for their antiproliferative efficacy on hepatic cancer cell lines (HepG2) and breast cancer cell lines (MCF-7); also, their effects on normal cell lines (BALB/3T3) were studied. Moreover, in silico molecular docking studies were studied for the compounds against the binding site of Homo sapiens Rho7 protein. The pharmacokinetic properties of the newer compounds were also evaluated using various computational tools. The compounds showed interesting interactions with satisfactory docking scores to the target Rho7; thus, they may act as promising potent drug candidates against cancer.     

Synthesis,characterization and biological evaluation of some novel sulfonylthiosemicarbazides

Abstract

A series of thiosemicarbazides were synthesized and structurally characterized by spectroscopic techniques (NMR, FT-IR) besides elemental analysis. These compounds were evaluated for their cytotoxicity against human breast cancer cell line MCF7 and prostate cancer cell line PC3 and nonmalignant fibroblast L929 cell line by MTT assay. Among the compounds, N-[2-(4-chlorophenyl)ethyl]-2-[(4-methylphenyl)sulfonyl]hydrazinecarbothioamide (3d) and 2-[(4-methylphenyl)sulfonyl]-N-[4-(trifluoromethoxy)phenyl]hydrazinecarbothioamide (3f) were found to display significant cytotoxicity with IC₅₀ of 13.87?μM (against PC3 cell line) and 1.47?μM (against MCF7 cell line), respectively. These compounds were non-cytotoxic to normal cell line with IC₅₀>100?μM. Western blotting studies demonstrated that compound 3f induced apoptosis and caused cell death in the MCF7 and PC3 cell lines via an increase in Bax protein expression and a slight decrease in Bcl-2 protein expression. The gene expression ratio Bax/Bcl-2 showed the induction of mitochondrial apoptosis in cancer cell lines. All of synthesized compounds have also been tested for antioxidant activity and all compounds achieved strong inhibition of the DPPH radical. These findings showed that compound 3f, displays potential to be further explored in the development of new anticancer agents.     

Potential COVID-19 Drug Candidates Based on Diazinyl-Thiazol-Imine Moieties: Synthesis and Greener Pastures Biological Study

A novel series of 1-aryl-N-[4-phenyl-5-(arylazo)thiazol-2-yl)methanimines has been synthesized via the condensation of 2-amino-4-phenyl-5-arylazothiazole with various aromatic aldehydes. The synthesized imines were characterized by spectroscopic techniques, namely ¹H and ¹³C-NMR, FTIR, MS, and Elemental Analysis. A molecular comparative docking study for 3a–f was calculated, with reference to two approved drugs, Molnupiravir and Remdesivir, using 7BQY (M^pro; PDB code 7BQY; resolution: 1.7 A°) under identical conditions. The binding scores against 7BQY were in the range of −7.7 to −8.7 kcal/mol for 3a–f. The high scores of the compounds indicated an enhanced binding affinity of the molecules to the receptor. This is due to the hydrophobic interactions and multi-hydrogen bonds between 3a–f ligands and the receptor’s active amino acid residues. The main aim of using in silco molecular docking was to rank 3a–f with respect to the approved drugs, Molnupiravir and Remdesivir, using free energy methods as greener pastures. A further interesting comparison presented the laydown of the ligands before and after molecular docking. These results and other supporting statistical analyses suggested that ligands 3a–f deserve further investigation in the context of potential therapeutic agents for COVID-19. Free-cost, PASS, SwissADME, and Way2drug were used in this research paper to determine the possible biological activities and cytotoxicity of 3a–f.     

Novel Perbutyrylated Glucose Derivatives of (–)-Epigallocatechin-3-Gallate Inhibit Cancer Cells Proliferation by Decreasing Phosphorylation of the EGFR: Synthesis,Cytotoxicity, and Molecular Docking

Lung cancer is one of the most commonly occurring cancer mortality worldwide. The epidermal growth factor receptor (EGFR) plays an important role in cellular functions and has become the new promising target. Natural products and their derivatives with various structures, unique biological activities, and specific selectivity have served as lead compounds for EGFR. D-glucose and EGCG were used as starting materials. A series of glucoside derivatives of EGCG (7–12) were synthesized and evaluated for their in vitro anticancer activity against five human cancer cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480. In addition, we investigated the structure-activity relationship and physicochemical property–activity relationship of EGCG derivatives. Compounds 11 and 12 showed better growth inhibition than others in four cancer cell lines (HL-60, SMMC-7721, A-549, and MCF), with IC₅₀ values in the range of 22.90–37.87 μM. Compounds 11 and 12 decreased phosphorylation of EGFR and downstream signaling protein, which also have more hydrophobic interactions than EGCG by docking study. The most active compounds 11 and 12, both having perbutyrylated glucose residue, we found that perbutyrylation of the glucose residue leads to increased cytotoxic activity and suggested that their potential as anticancer agents for further development.     

New furochromone derivatives as promising in-vitro anti-proliferative agents toward HepG-2 and MCF-7 cell lines with molecular docking studies

Based on the considerable features of the multicomponent reactions (MCRs) in the field of organic and medicinal chemistry, the present work was designed to synthesize a new series of imidazole, pyridine, and pyrimidine derivatives using MCRs to obtain new anti-proliferative agent beside exploration of their interaction mechanism by molecular docking technique. MCRs of furochromone carbaldehyde 1 , benzoin, and ammonium acetate afforded the corresponding 2,4,5-trisubstituted imidazole 2 . However, MCRs of 1 with benzoin, amine derivatives, and ammonium acetate yielded the corresponding 1,2,4,5-tetrasubstituted imidazole 3a,b . In addition, pyridine 4a,b-5a,b and pyrimidine derivatives 6a,d were synthesized via condensation of 1 with different carbonyl compounds and ammonium acetate or benzyl urea, respectively. The in-vitro anti-Proliferative activities of the new furochromone derivatives were screened toward MCF-7 and HepG-2 cancer cell lines as well as the normal cell line (human normal melanocyte, HFB4) in comparison to the known anticancer drugs: 5-fluorouracil and doxorubicin using MTT assay. Compounds 5a and 5b revealed effective anti-proliferative activity against MCF-7 cell lines with IC ₅₀ 18 and 22 μg/mL, respectively, compared to 5-fluorouracil (IC ₅₀ of 13 μg/mL). However, compounds 6a-d exhibited potent activity against HepG-2 cancer cell lines of IC ₅₀ ranging from 18 to 20 μg/mL compared to doxorubicin (IC ₅₀ of 14 μg/mL). Moreover, the binding mode of the most active furochromones 5a,b and 6a-d inside the active site of the epidermal growth factor receptor (EGFR) kinase enzyme (PDB ID: 5CAV) were studied using molecular docking technique. Compounds 6b,c showed excellent docking results compared to the known EGFR inhibitors ( 4ZQ ).