Multistep synthesis and screening of heterocyclic tetrads containing furan,pyrazoline, thiazole and triazole (or oxadiazole) as antimicrobial and anticancer agents

In the present study novel heterocyclic tetrads containing furan, pyrazoline, thiazole and triazole (or oxadiazole) (1, 2, 3, 4a-e and 5a-e) were designed and synthesized and investigated for their antimicrobial (against selected bacteria and fungi) and anticancer potential. The molecules 4e and 5e containing 4-fluoro phenyl and 4-fluoro benzyl substituents showed promising antimicrobial (antibacterial and antifungal activities with MICs ranging between 0.5 and 8 µg/mL. Compounds 3 exhibited potent anticancer activity with an IC₅₀ value of 0.49 ± 1.45 µM against the human gastric cancer cell line (BGC-823) whereas compound 4e displayed an IC₅₀ value of 0.65 ± 0.53 µM against breast cancer (MCF-7) cell line respectively. All compounds showed selective toxicity against the cancer cell lines compared to human normal liver cell lines. Molecular docking studies of the most potent compounds (3 and 4e) against selected microbial and cancer proteins revealed the crucial binding interactions of the potent compounds with the target enzymes. Compounds 3 and 4e are promising lead molecules to be developed as potential drug candidates.     

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.     

Evaluation of structural,spectral characterization and in vitro cytotoxic activity studies of some polycyclic aromatic compounds

The present study aims to introduce three known and three new stable polycyclic aromatic compounds synthesized. With MALDI-Mass, ¹H and ¹³C NMR spectroscopy, all new compounds were characterized. In the DMF solution were carried out the electrochemical and photophysical properties of the polyaromatic compounds. The compounds are highly fluorescent showing green-red emission when excited at one single wavelength. For the compound 3, it was shown that the highest Stokes Shift (191 nm) appeared which may be due to the excited state energy transfer. The compounds also indicated the blue-orange region of the electromagnetic spectrum strong emission bands. Additionally, compounds 1, 3, 4, and 5 were investigated for their in vitro cytotoxic activities against PC-3 prostate cancer cells, L-929 non-cancerous cells, and MDA-MB-231 breast cancer for 24 h, 48 h and 72 h. The results obtained from the experiment demonstrated that compounds had different cytotoxic activity against cell lines. Compound 3 was indicated to be inactive against L-929 cells and MDA-MB-231 cancer cells, whereas compounds 1, 4 and 5 indicated a dose and time-dependent cytotoxic activity against PC-3, MDA-MB-231, and L-929 cell lines. It was found that the most sensitive cells to compound 5 were MDA-MB-231 human breast cancer cells. Additionally, it became clear that compounds 1 and 3 had significant selectivity for human PC-3 prostate cancer cells, and compounds 1, 4 and 5 had considerable selectivity for human MDA-MB-231 breast cancer cells. Also, the quantum chemical examinations of six organic compounds were conducted at the B3LYP/6-31G level in the gas phase and water. According to calculated results, compound 5 was found to be the best candidate for NLO applications.     

Artemisinin-isatin hybrids with potential antiproliferative activity against breast cancer

Three series of artemisinin-isatin hybrids 8a-i, 10a-c and 11a-e were designed, synthesized and evaluated for their antiproliferative activity against breast cancer cells (MCF-7, MDA-MB-231 and doxorubicin-resistant MCF-7 (MCF-7/DOX)), as well as the cytotoxicity towards normal MCF-10A breast cells. The preliminary results showed that a significant part of the synthesized hybrids (IC₅₀: 20.7–99.9 µM) were active against both drug-sensitive and doxorubicin-resistant breast cancer cell lines. The structure–activity relationship illustrated that the linker between artemisinin and isatin moieties as well as the substituents on C-3 and C-5 position of isatin motif had great influence on the activity. In particular, hybrids 11c,d were found to be most active against all tested breast cancer cell lines, and their activity was not inferior to that of doxorubicin. Therefore, hybrids 11c,d could serve as useful templates for the development of novel anti-breast cancer agents.     

Antitubercular and antioxidant activities of hydroxy and chloro substituted chalcone analogues: Synthesis,biological and computational studies

A series of chalcone analogues (1–15) were synthesized by Claisen-Schmidt condensation in good yields (70–95%) and characterized by FT-IR, ¹H NMR and mass spectral methods. Additionally, compounds 3 and 7 were characterized by ¹³C NMR. Antitubercular and antioxidant activities of the chalcones were evaluated by MABA and DPPH free radical assays. In MABA assay analogues 3 (MIC = 14 ± 0.11 µM) and 11 (MIC = 14 ± 0.17 µM) bearing fluorine and methoxy groups at para and meta positions were 1.8-times more active than the standard pyrazinamide (MIC = 25.34 ± 0.22 µM). The chalcone analogues such as compound 7 (IC₅₀ = 4 ± 1 µg/mL) containing electron releasing groups such as OH at ortho position had slightly more antioxidant activity than Gallic acid (IC₅₀ = 5 ± 1 µg/mL). The potential compounds 3, 7, 9 and 11 were less selective and toxic against human live cell lines-LO2. Further, molecular docking results of chalcones against anti-tubercular drug target isocitrate lyase (PDB ID: 1F8M) revealed that compound 3 and 11 shown least binding energies as ?7.6, and ?7.5 kcal/mol are in line with in vitro MABA assay, suggesting that these compounds 3 and 11 are strong inhibitor of isocitrate lyase. SwissADME programme estimated the drug likeliness properties of compounds 3, 7, 9 and 11. The lead molecules arisen through this study helps to develop new antitubercular and antioxidant agents.     

Design,synthesis, biological evaluation and in silico studies of novel 1,2,3-triazole linked benzoxazine-2,4-dione conjugates as potent antimicrobial,antioxidant and anti-inflammatory agents

In an attempt to rationalize the search for new potential anti-inflammatory and anti-infection agents, a new series of 1,4-and 1,5-disubstituted 1,2,3-triazoles linked benzoxazine conjugates have been synthesized via “Click Chemistry” reaction, were designed, synthesized and characterized by means of spectral and elemental data. The newly synthesized compounds have been assessed for their antimicrobial, antioxidant and anti-inflammatory potential. Results revealed that all synthesized compounds display superior activities to the standard drug against different bacterial strains especially S. aureus, M. luteus, and P. aeruginosa, with good to moderate activity towards the tested E. coli bacteria, in respect to the commercial antibiotic, tetracycline. Moreover, the antifungal activity was screened against C. albicans and C. krusei yeasts and results demonstrate potent activity as compared to the standard drug, ampicillin. The antioxidant activity was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assays, whose results indicate that analogues 4a (IC₅₀ 1.88 ± 0.07 µM and 2.17 ± 0.02) followed by 4b (IC₅₀ 2.19 ± 0.09 µM and 2.38 ± 0.43 µM), 4d (IC₅₀ 2.30 ± 0.01 µM and 4.07 ± 0.57 µM), and 4f (2.98 ± 0.02 µM and 3.80 ± 0.01 µM), respectively, exhibited the strongest activity when compared to the standard reference, butylated hydroxytoluene (BHT) (3.52 ± 0.08 µM and 4.64 ± 0.11 µM). In addition, their anti-inflammatory activity was assessed using the xylene-induced ear edema standard technique and the results demonstrated the potency of 4a, 4b and 4d as excellent anti-inflammatory agents. Preliminary structure–activity relationship studies (SARs) provide those biological activities can be modulated by the presence of unsubstituted aromatic ring as well as the position of substituents on the phenyl moiety via electron withdrawing groups (EWGs) or electron donating groups (EDGs) effects. Docking studies on the most promising compounds 4a, 4b, and 4d into the active sites of S. aureus tyrosyl-tRNA synthetase, Candida albicans N-Myristoyltransferase, Human COX-2 enzyme, and Human Peroxiredoxin 5 revealed good binding profiles with the target proteins. The interaction's stability was further assessed using a conventional atomistic 100 ns dynamic simulation study. Hence, our results recommended the rationalized targets 4a, 4b and 4d, to be promising lead candidates for the discovery of novel dual anti-inflammatory and anti-infection agents.     

Design and synthesis of some novel pyridothienopyrimidine derivatives and their biological evaluation as antimicrobial and anticancer agents targeting EGFR enzyme

A new series of pyridothienopyrimidine derivatives was designed and evaluated as antimicrobial and anticancer agents. The target compounds were synthesized starting with 3-aminothieno[2,3-b]pyridine-2-carboxamide derivative 1 which underwent cyclocondensation reaction with aromatic aldehydes to give the key intermediates 2a,b. By further treatment of 2a,b with various reagents, the target 2,4-disubstituted-pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidines 3a,b–11a,b were obtained. To evaluate the antimicrobial activity of the new compounds, they were tested against five bacterial and five fungal strains. Compounds 6c, 8b, 9a and 9b revealed the most significant antimicrobial activity against the tested microorganisms with MIC values range (4–16 μg/mL). Also, compounds 2a,b–11a,b were screened for their in vitro cytotoxic activity against HepG-2 and MCF-7 cancer cell lines compared with doxorubicin and cisplatin as references drugs. Moreover, compounds (2b, 4a, 6a, 7b, 7c and 9a) which exhibited the most potent anticancer activity, were further subjected to EGFR^WT enzyme inhibition assay utilizing erlotinib as a standard drug. The compounds 6a, 7b, 7c and 9a which showed the most promising suppression effects were also evaluated as inhibitors against the mutant forms EGFR^L858R and EGFR^T790M. The 4-aminopyrazolone analogue 9a showed superior anticancer activity against both HepG-2 and MCF-7 cell lines (IC50 = 1.27, 10.80 μM, respectively) and more potent enzymatic inhibition activity against EGFR^WT and its mutant forms EGFR^L858R and EGFR^T790M than that obtained by erlotinib (IC₅₀ = 0.021, 0.053, 0.081 µM, respectively, IC_50erlotinib; 0.027, 0.069, 0.550 µM, respectively). Finally, the molecular docking study showed good binding patterns of the most active compounds with the prospective target EGFR^WT.     

One-pot multicomponent synthesis of novel 3, 4-dihydro-3-methyl-2(1H)-quinazolinone derivatives and their biological evaluation as potential antioxidants,enzyme inhibitors,antimicrobials, cytotoxic and anti-inflammatory agents

A series of novel 3, 4-dihydro-3-methyl-2(1H)-quinazolinone derivatives with substituted amine moieties (1–13) and substituted aldehyde (S) were designed and synthesized by a reflux condensation reaction in the presence of an acid catalyst to get N-Mannich bases. Mannich bases were evaluated pharmacologically for their antioxidant, α-amylase enzyme inhibition, antimicrobial, cell cytotoxicity and anti-inflammatory activities. Most of the compounds exhibited potent activities against these bioassays. Among them, SH1 and SH13 showed potent antioxidant activity against DPPH free radical at IC₅₀ of 9.94 ± 0.16 µg/mL and 11.68 ± 0.32 µg/mL, respectively. SH7, SH10 and SH13 showed significant results in TAC and TRP antioxidant assays, comparable to that of ascorbic acid. SH2 and SH3 showed potent activity in inhibiting α-amylase enzyme at IC₅₀ of 10.17 ± 0.23 µg/mL and 9.48 ± 0.17 µg/mL, respectively, when compared with acarbose (13.52 ± 0.19 µg/mL). SH7 was the most active against gram-positive and gram-negative bacterial strains, SH13 being the most potent against P. aeruginosa by inhibiting its growth up to 80% (MIC = 11.11 µg/mL). SH4, SH5 and SH6 exhibited significant activity against some fungal strains. Among the thirteen synthesized compounds (SH1-SH13), four were screened out based on the results of brine shrimp lethality assay (LD₅₀) and cell cytotoxicity assay (IC₅₀), to determine their anti-cancer potential against Hep-G2 cells. The study was conducted for 24, 48, and 72 h. SH12 showed potent results at IC₅₀ of 6.48 µM at 72 h when compared with cisplatin (2.56 µM). An in vitro nitric oxide (NO) assay was performed to shortlist compounds for in vivo anti-inflammatory assay. Among shortlisted compounds, SH13 exhibited potent anti-inflammatory activity by decreasing the paw thickness to the maximum compared to the standard, acetylsalicylic acid (ASA).     

Design,synthesis of new novel quinoxalin-2(1H)-one derivatives incorporating hydrazone,hydrazine, and pyrazole moieties as antimicrobial potential with in-silico ADME and molecular docking simulation

A series of 6-(morpholinosulfonyl)quinoxalin-2(1H)-one based hydrazone, hydrazine, and pyrazole moieties were designed, synthesized, and evaluated for their in vitro antimicrobial activity. All the synthesized quinoxaline derivatives were characterized by IR, NMR (¹H /¹³C), and EI MS. The results displayed good to moderate antimicrobial potential against six bacterial, and two fungal standard strains. Among the tested derivatives, six quinoxalin-2(1H)-one derivatives 4a, 7, 8a, 11b, 13, and 16 exhibited a significant antibacterial activity with MIC values (0.97–62.5 µg/mL), and MBC values (1.94–88.8 µg/mL) compared with Tetracycline (MICs = 15.62–62.5 µg/mL, and MBCs = 18.74–93.75 µg/mL), and Amphotericin B (MICs = 12.49–88.8 µg/mL, and MFC = 34.62–65.62 µg/mL). In addition, according to CLSI standards, the most active quinoxalin-2(1H)-one derivatives demonstrated bactericidal and fungicidal behavior. Moreover, the most active quinoxaline derivatives showed a considerable antibacterial activity with bactericidal potential against multi-drug resistance bacteria (MDRB) strains with MIC values ranged between (1.95–15.62 µg/mL), and MBC values (3.31–31.25 µg/mL) near to standard Norfloxacin (MIC = 0.78–3.13 µg/mL, and MBC = 1.4–5.32 µg/mL. Further, in vitro S. aureus DNA gyrase inhibition activity were evaluated for the promising derivatives and displayed potency with IC₅₀ values (10.93 ± 1.81–26.18 ± 1.22 µM) compared with Ciprofloxacin (26.31 ± 1.64 µM). Interestingly, these derivatives revealed as good immunomodulatory agents by a percentage ranging between 82.8 ± 0.37 and 142.4 ± 0.98 %. Finally, some in silico ADME, toxicity prediction, and molecular docking simulation were performed and showed a promising safety profile with good binding mode.     

Design,synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects

A series of novel thiazolidine-4-one derivatives was synthesized by reacting 1,4-disubstituted hydrazine carbothioamides with diethyl azodicarboxylate. The structures were confirmed by spectroscopic data as well as single-crystal X-ray analyses. The antiproliferative activity of the synthesized compounds was investigated against four human cancer cell lines using an MTT assay. Compounds 5d, 5e, and 5f revealed the most potent antiproliferative activity with GI₅₀ values ranging from 0.70 µM to 1.20 µM, compared to doxorubicin GI₅₀ value = 1.10 µM. Compounds 5d, 5e, and 5f were further investigated for their inhibitory activities against CDK2 and EGFR as potential targets for their molecular mechanism. Compounds 5e and 5f have showed potent inhibitory activity to CDK2 enzyme with IC₅₀ values of 18 and 14 nM, which is more potent than the reference dinaciclib (IC₅₀ = 20 nM). Moreover, compounds 5e and 5f were the most potent EGFR inhibitors, with IC₅₀ values of 93 and 87 nM, respectively, compared to the reference erlotinib (IC₅₀ = 70 nM). In addition, the most potent derivatives were tested for their apoptotic activity against caspases 3, 8, and 9, and the results showed that compounds 5d, 5e, and 5f revealed a greater increase in active caspases 3,8 and 9 than doxorubicin. Also, compounds 5d, 5e, and 5f elevated cytochrome C levels in the MCF-7 human breast cancer cell line by about 15.5, 15.8, and 16.5 times, respectively. Finally, a molecular docking study was performed to investigate the binding sites of these compounds within the active sites of CDK2 and EGFR targets, and the results confirmed that the most potent CDK2 and EGFR inhibitor 5h also have showed the highest docking score.     

Synthesis and cytotoxic activity of new indolylpyrrole derivatives

The current approach described the synthesis of a new series of indolylpyrrole derivatives through multicomponent reaction of α-cyano chalcones, appropriate aldehydes, and ammonium acetate in refluxed acetic acid. The chemical structures of the designed compounds were confirmed with spectroscopic data and elemental analysis and then tested for their in vitro cytotoxic activity by SRB assay method towards three cell lines involving human Prostate adenocarcinoma; metastatic cells (PC-3), human ovary adenocarcinoma (SKOV3) and human dukes' type B, colorectal adenocarcinoma (LS 174 T). Most significant activity provided with compounds 5c, 5h and, 5j against prostate cancer cells (PC-3) with IC50s of 3.30 ± 0.20, 3.60 ± 0.10, and 3.60 ± 0.90 µg/ml, respectively. In human ovarian carcinoma (SKOV3), the compounds 5a, and 5i have stronger cytotoxicity with IC50s of 1.20 ± 0.04, 1.90 ± 0.50 µg/ml, respectively than the standard doxorubicin (IC50 = 2.20 ± 0.02 µg/ml). On the other hand, only compound 5a has the ability to diminish the viability of LS174T cells in an active manner with IC50 2.80 ± 0.10 µg/ml. Consequently, this effort offers groundwork for additional examination of nominated indolylpyrroles as antiproliferative agents.     

Syntheses,characterizations, crystal structures,DFT/TD-DFT,luminescence behaviors and cytotoxic effect of bicompartmental Zn (II)-dicyanamide Schiff base coordination polymers: An approach to apoptosis,autophagy and necrosis type classical cell death

Two new Zn (II)-dicyanamide (dca) 1-D chain coordination polymers (CPs), [Zn (L^OMe)(μ₁-dca)(μ_1,5-dca)]_n (1) and [Zn (L^OEt)(μ₁-dca)(μ_1,5-dca)]_n (2) have been successfully synthesized from bicompartmental Schiff base ligands N,N^′-Bis(3-methoxysalicylidenimino)-1,3-diaminopropane (H₂L^OMe), N,N^′-Bis(3-ethoxysalicylidenimino)-1,3-diaminoproane (H₂L^OEt) respectively and structurally characterized using various spectroscopic protocols like ¹H NMR, IR, Raman, UV–Vis, fluorescence as well as elemental analysis, TGA, PXRD and SCXRD studies. X-ray single crystal study revealed that both the complexes have two different geometrical arrangement of Zn metal centres with distorted square pyramidal Zn(2) and trigonal prismatic geometry Zn(1). Ab-initio DFT (Density functional theory) has been executed at B3LYP (Becke, 3-parameter, Lee-Yang-Parr) using DGDVP (Diffuse gradient double valence polarised) basis set to explain FMO (Frontier molecular orbital), TD-DFT (Time-dependent density functional theory) and photovoltaic efficiency in Dye Sensitized Solar Cell (DSSC). Hirshfeld surface (HS) and 2D fingerprint plot analyses are shed more light on the non-covalent supramolecular interactions. The steady state and time-resolved fluorescence measurements have been conducted in DMSO and solid-state. CPs exhibited bi-exponential decay in DMSO as well as solid-state where fluorescence behaviors are mainly intra-ligand (π → π^*) in nature with lifetimes in the range (1.11–1.06 ns). In particular, in vitro cytotoxic activities were evaluated towards MCF7 (breast cancer) cell line, MDA-MB-231 (breast carcinoma) cell line and MCF10A (breast epithelial) cell line using MTT assay. CP 1 had lower cytotoxic effect against MCF7 (20 μM), MDA-MB-231 (15 μM) cell lines in comparison with cisplatin (42.2 ± 8, 128.2 ± 7 μM). CP 1 induced classical cell death apoptosis, autophagy and necrosis. Lower IC₅₀ value of CP 1 against MDA-MB-231 cell line provide new insights in the development of cancer therapeutics.     

Microwave assisted synthesis of 2-amino-4-chloro-pyrimidine derivatives: Anticancer and computational study on potential inhibitory action against COVID-19

We report microwave synthesis of seven unique pyrimidine anchored derivatives (1–7) incorporating multifunctional amino derivatives along with their in vitro anticancer activity and their activity against COVID-19 in silico. 1–7 were characterized by different analytical and spectroscopic techniques. Cytotoxic activity of 1–7 was tested against HCT116 and MCF7 cell lines, whereby 6 exhibited highest anticancer activity on HCT116 and MCF7 with EC₅₀ values of 89.24 ± 1.36 µM and 89.37 ± 1.17 µM, respectively.Molecular docking was performed for derivatives (1–7) on main protease for SARS-CoV-2 (PDB ID: 6LU7). Results revealed that most of the derivatives had superior or equivalent affinity for the 3CLpro, as determined by docking and binding energy scores. 6 topped the rest with highest binding energy score of ?8.12 kcal/mol with inhibition constant reported as 1.11 µM. ADME, drug-likeness, and pharmacokinetics properties of 1–7 were tested using Swiss ADME tool. Toxicity analysis was done with pkCSM online server.All derivatives showed high GI absorption. Except 1 and 3, all derivatives showed blood brain barrier permeability. Most derivatives showed negative logKp values suggesting derivatives are less skin permeable and bioavailability score of all derivatives was 0.55. The toxicity analysis demonstrated that all derivatives have no skin sensitization properties. 6 and 7 showed maximum tolerated dose (Human) values of ?0.03 and ?0.018, respectively and absence of AMES toxicity.     

New benzoxazole-based sulphonamide hybrids analogs as potent inhibitors of α-amylase and α-glucosidase: Synthesis and in vitro evaluation along with in silico study

The development of drugs resistance in diabetes mellitus is a growing clinical problem, creates many challenges for patient. To overcome these problems, there is a serious deficiency of anti-diabetic agents, may be synthesized that inhibit alpha amylase and alpha glucosidase activity. Here, we have design and synthesized benzoxazole based sulphonamide derivatives and evaluated for their anti-diabetic activity. Twenty-two benzoxazole based sulphonamide derivatives were synthesized by reacting 2-aminophenol with carbon disulphide in the presence of base (Et3N) to obtained 2-marcapto benzoxazole which was further dissolved in ethanol by slow addition of different substituted phenacyl bromide in the presence of triethylamine, afforded varied S-substituted benzoxazole products. These products were dissolved in ethanol and hydrazine hydrate was added an excess in the presence of acetic acid to gives Schiff base. This Schiff base products were further dissolved in THF along with different substituted benzene sulphonyl chloride followed by addition of few drops of Et3N, yielded benzoxazole based sulphonamide derivatives (1–22). Moreover, SAR was established for the synthesized compounds and molecular docking studies were conducted for the potent moieties in order to explore the binding modalities of analogs. Among the tested series few analogues were found few folds better potential than standard drug but analog 1 (IC₅₀ = 1.10 ± 0.20 µM, 1.20 ± 0.30 µM), showed promising anti-diabetic activity against α-amylase and α-glucosidase (11.12 ± 0.15 µM and 11.29 ± 0.07 µM respectively).     

Design,synthesis and docking studies of new hydrazinyl-thiazole derivatives as anticancer and antimicrobial agents

Increase in the number of infections caused by pathogenic microbes in cancer patients has prompted the searcher to invest in the development of agents having dual anticancer and antimicrobial properties. The present study is concerned with synthesis and screening for anticancer and antimicrobial activity of a series of 5-hydrazinyl-2-(2-(1-(thien-2-yl)ethylidene)hydrazinyl)thiazole derivatives. The structure elucidation of the synthesized hydrazinyl thiazole derivatives was illustrated by spectroscopic and elemental analysis. All the newly synthesized compounds 5a-p were evaluated for in-vitro cytotoxic activity against breast carcinoma (MCF-7 cell line), hepatocellular carcinoma (HePG-2) and colorectal cancer (HCT-116) cell lines using MTT assay method. Compounds 5 g, 5h showed broad spectrum activity against three cancer cell lines with IC₅₀ ranged from 3.81 to 11.34 µM in compared to the reference drug Roscovitine (IC₅₀ = 9.32 to 13.82 µM), while compounds 5 l and 5 m were found to be more selective against HePG-2 and HCT-116 cell line (IC₅₀ = 9.29 and 8.93 µM respectively) and compound 5j was more selective against HePG-2 and MCF-7 cell lines (IC₅₀ = 6.73 and 10.87 µM respectively). The inhibitory activity of the most promising compounds was tested against the EGFR and ARO enzymes and were further tested for apoptosis and Annexin V/PI staining. The results of enzyme-based tests revealed that the tested compound 5j has a dual inhibitory effect on the EGFR and ARO enzymes with IC₅₀ = 82.8 and 98.6 nM respectively in compared to the reference drugs Erlotinib and Letrozole (IC₅₀ = 62.4 and 79 nM respectively). Furthermore, the majority of the tested hydrazinyl thiazole derivatives exhibited significant antimicrobial activity against the used pathogenic microbes species. Compounds 4b, 5h, 5j and 5 m exerted a good antibacterial and antifungal activity against all tested pathogenic microbes. Therefore, it was concluded that compounds 5 h, 5j and 5 m proved to possess dual anticancer and antimicrobial agent and may serves as a useful lead compounds in search for further modification or derivatization to give more potent and selective agents.     

Design,synthesis, docking and mechanistic studies of new thiazolyl/thiazolidinylpyrimidine-2,4-dione antiproliferative agents

In this article, we display on the synthesis and biological evaluation of a new series of thiazolylpyrimidine 3a-l and thiazolidinylpyrimidine derivatives 5a-e. The structures of the new compounds were confirmed by using different spectral techniques including NMR, IR, mass spectroscopy in addition to elemental analyses. The cell viability of the new compounds was assessed against normal human mammary gland epithelial (MCF-10A) cell line. Data revealed that none of the compounds examined exhibited cytotoxic effects, and the cell viability for the compounds examined at 50 µM was greater than 87%. The antiproliferative activity of 3a-l and 5a-e was evaluated against four human cancer cell lines where the compounds showed promising activity. The most potent derivatives were compounds 3a, 3c, 3f, 3i, and 5b with GI₅₀ values ranging from 0.90 µM to 1.70 µM against the four cancer cell lines in comparison to doxorubicin (GI₅₀ = 1.10 µM). Compounds 3a, 3c and 3i showed potent antiproliferative activity with dual inhibitory action against EGFR and BRAF^V600E. Compounds 3a, 3c, and 3i demonstrated promising AutoDock scores towards EGFR and BRAF^V600E with values of ? 9.1 and ? 8.6, ?9.0 and ? 8.5, and ? 8.4 and ? 8.0 kcal/mol, respectively. The physicochemical and pharmacokinetic characteristics of 3a, 3c, and 3i were anticipated, demonstrating their oral bioavailability.     

Synthesis of novel [1,2,3]triazolo[4′,5′:3,4]pyrrolo[1,2-a]thieno[2,3-d] pyrimidines: Potent EGFR targeting anti-breast cancer agents

In this study, we designed and synthesized several novel fused [1,2,3]triazolo [4′,5′:3,4]pyrrolo[1,2-a]thieno[2,3-d]pyrimidine derivatives using in a single [3 + 2] reaction cycloaddition reaction of 3-(3-iodoprop-2-yn-1-yl)thieno[2,3-d]pyrimidin-4(3H)-one ( 4 ) followed by C-C bond coupling with various aryl azides in a PEG-400 medium. All of the newly synthesized compounds were evaluated in vitro for EGFR kinase inhibitory action as well as anti-breast cancer activity against MDA-MB-231 and MCF-7 breast cancer cell lines. When compared to the reference molecule, erlotinib, the majority of the compounds demonstrated adequate efficacy. The most promising compounds, 5g and 5i , demonstrated excellent anticancer activity against both cancer cell lines, with IC₅₀ values ranging from 04.17 ± 0.55 to 8.65 ± 0.89 μM, respectively, as well as excellent kinase inhibitory activities (EGFR: IC₅₀ = 0.467 ± 0.063 and 0.412 ± 0.081 μM). The in silico studies of five potent compounds 5f , 5g , 5h , 5i , and 5k were also carried out to identify the interactions against the EGFR receptor and found that the energy calculations were covenant with the obtained IC₅₀ values.     

Synthesis,characterization and biological evaluation of purine nucleoside analogues

We present a convenient route for the synthesis of C6-amino-C5′-N-cyclopropyl carboxamido-C2-alkynylated purine nucleoside analogues 11a–g via Sonogashira coupling reaction. The nine step synthesis is easy to perform, employing commercially available reagents. Compound 9 is used as key intermediate for the synthesis of analogues 11a–g. Synthetic intermediates and final products are appropriately characterized by IR, ¹H NMR, ¹³C NMR and Mass. The modified nucleoside analogues 11a–g is evaluated for in vitro anticancer activity against MDA-MB-231 and Caco-2 cell lines. Screening data reveals that compounds 11b and 11e displayed potent IC₅₀ value of 7.9, 6.8 µg/mL respectively against MDA-MB-231 and of 7.5, 8.3 µg/mL respectively against Caco-2 than the standard drug doxorubicin, thus establishing the potential anti-cancer properties of these newer derivatives.     

Discovery of novel indene-based hybrids as breast cancer inhibitors targeting Hsp90: Synthesis,bio-evaluation and molecular docking study

Inhibition of Heat-shock protein 90 (Hsp90) is considered an attractive route in fighting against cancer proliferation. Herein, new indene derivatives targeting Hsp90 were synthesized, and biologically evaluated. The new series of indeno-pyrimidine and indeno-pyridine were synthesized from the reaction of indene-enaminone with various heterocyclic amines and active methylene derivatives. Two breast cancer cell lines were used to examine the new compounds in vitro for their anticancer activity, namely, MCF-7 and MDA-MB231 cancer cells. The new indene derivatives 8a-c, 17a, and 25 displayed significant antitumor effect especially on MCF-7 cell line compared to doxorubicin. Derivative 8a was further subjected to Hsp90 enzyme assay aiming to ensure the inhibitory potential of such compound on Hsp90, it displayed IC₅₀ = 18.79 ± 0.68 nM relative to Alvespimycin as a reference drug. Finally, molecular modeling of the most active compounds in the Hsp90 binding site was done presenting agreement with the in vitro anti-Hsp90 activity.     

Design,synthesis and biological evaluation of novel quinazoline derivatives as potential NF-κb inhibitors

A series of novel 4-aminoquinazoline derivatives were designed, synthesized and biological properties on nuclear factor-kappaB (NF-κb) pathway inhibitory and potential in vitro anti-proliferation against breast cancer lines were also evaluated. Among them, LU1501 exhibited potent inhibition with IC₅₀ values in SK-BR-3 (10.16 ± 0.86 µM) and HCC1806 (10.66 ± 1.01 µM) cell lines. In vivo studies in breast cancer tumor model proved the correlation between anticancer activity of LU1501 and proliferation inhibition through the NF-κb signal pathway. The molecular docking studies also portrayed the potential binding mechanism between LU1501 and the key proteins of p65 and IkBα in NF-κb pathway. Accordingly, compound LU1501 could serve as a potent agent against breast cancer for further investigation.