الفهرس 
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Abstract
Benzofuran moiety is included in many bioactive and biologically active compounds. There are many benzofuran derivatives which are approved as antihypertensive, anticancer, antimicrobial, anti-arrhythmia, analgesic, anti-inflammatory, etc... Molecular hybridization, leading approach in drug-discovery techniques, is used in this work to hybridize between benzofuran and thiazole, piperazine, piperidine, aryl azo, dithiocarbamate, thiosemicarbazone/ semicarbazone and benzylidene moieties. In present work, three series of benzofuran derivatives have been designed and synthesized via three schemes: Scheme 1: illustrate the preparation of benzofuranyl-thiazole derivatives 125(a-e)-128 via Hantzsch’s thiazole synthesis by condensation of α-haloketones and thioamides. Scheme 2: illustrate the preparation of benzofuran-piperazine hybrids 142(a,b) via Willgerodt’s reaction by 1-(benzofuran-2-yl)ethan-1-one, appropriate piperazine derivative and metallic sulfur in glycerol containing K2CO3 as a solvent. Also, the preparation of benzofuran-aryl hydrazone hybrids 146(a-f) by the reaction of enaminone 143 with appropriate aryldiazonium chloride 145(a-f). Moreover, the preparation of benzofuran- piperidine hybrid 147 via the reaction of enaminone 143 with piperidine. Scheme 3: illustrate the preparation of 2-(4-methoxyphenyl)-2-oxoethyl 2-[1-(benzofuran-2yl)ethylidene] hydrazinecarbodithioate (157) via the addition of CS2 and 2-bromo-4′-methoxyacetophenone to the hydrazone 156. Also, the preparation of benzofuran-thiosemicarbazone/ semicarbazone hybrid 158(a,b) via the reaction of hydrazone 156 appropriate isocyanate or isothiocyanate derivative. Moreover, the preparation of benzofuran- benzylidene hybrid 159(a-e)-160 via Schiff-base’s reaction by condensation of hydrazone 156 with appropriate aldehyde. The previously mentioned reactions resulted in twenty-six final compounds in addition to three intermediates that were previously reported. The synthesized molecules have been confirmed using 1H-NMR, 13C-NMR, 2D 1H-1H NOESY NMR, mass and IR spectroscopy. Anticancer activity of the newly synthesized compounds was evaluated against hepatocellular carcinoma (HePG2), mammary gland breast cancer (MCF-7), epithelioid carcinoma cervix cancer (Hela) and human prostate cancer (PC3). Compounds 125e,f, 126, 128, 157, 158b and 159c showed good to moderate activity against the assessed cells by IC50 values between 8.49 to 51.8 µM in comparison to DOX (4.17-8.87 µM). The most active anticancer compounds 125e, 126, 128 and 158b have posed further evaluation against enzymatic inhibition of PI3K and VEGRF-2. Compounds 125e and 158b is proposed to have PI3K and VEGRF-2 inhibitory activity as mechanism of action. Also, cell cycle arrest and induction of apoptosis in different phases of MCF-7 cells were assessed for compounds 125e and 126 cell cycle arrest and induction of apoptosis in different phases of Hela cells were assessed for compound 158b. Moreover, computational studies as molecular docking, binding affinity surface mapping, contact preference and physicochemical properties predication of the synthesized compounds 125e, 126, 128 and 158b ware performed against PI3K. The computational studies were performed using molecular operating environment software (MOE) and showed a good interaction with a crucial residue for inhibition. Antimicrobial activity was evaluated against Gram-positive isolates as Staphylococcus aureus and Bacillus cereus, Gram-negative isolate as Escherichia coli, Pseudomonas aeruginosa and antifungal potential against Candida albicans. (QS) inhibiting effects were detected using chromobacterium violaceum for investigating the mechanism of action of the synthesized compounds against resistant bacteria for facing antimicrobial resistance problem. Compound 146e showed outstanding anti Gram-positive activity with MIC values 8 and 256 µg/mL in Staphylococcus aureus and Bacillus cereus, respectively. Also, compounds 146c,e,f and 157 showed good anti Gram-negative activity with MIC value 512 µg/mL for all compounds. In addition, quorum sensing evaluation for the synthesized compounds was conducting where compounds 125d, 126, 127, 128, and 143 showed good QS inhibition (3, 3, 5, 2, and 7 mm).