Hamadeh Tarazi

Design, synthesis and biological evaluation of new pyrrolidine carboxamide analogues as potential chemotherapeutic agents for hepatocellular carcinoma

The successful targeting of different malignancies by OSU-2S, encouraged us to design and synthesize a novel series of pyrrolidine aryl carboxamide derivatives. In this context, we found that, the amide nature and tether length were found to be key determinant elements for the anticancer activity of these new and rigid analogues of OSU-2S. The most effective analogues induced apoptosis in cancer cells by a similar mechanism to that of OSU-2S, possibly via the activation of PKCδ in addition to their ability to induce cell cycle arrest and inhibition of cancer cell migration. Compound 10m, possesses anticancer potency comparable to that of OSU-2S when tested against cancer cell lines under study, and was found to be safer on normal cells. Furthermore, compound 10m, was found to be about 2-folds more potent than the anticancer drug Sorafenib in hepatocellular carcinoma (HCC). The newly developed compounds represent a therapeutically promising approach for the treatment of HCC.

Post-Ugi Cascade Transformations for Accessing Diverse Chromenopyrrole Collections

Employing a build/couple/pair strategy, a serendipitous one-pot protocol for the diastereoselective construction of diverse collections of chromenopyrroles is described. This methodology features an unprecedented five-step cascade including azomethine ylide generation followed by in situ intramolecular [3 + 2]-cycloaddition. Furthermore, this protocol was extended to access enantiopure chromenopyrroles using amino acids as chiral auxiliary. Moreover, postpairing reactions were employed to increase the diversity and complexity of our pilot compound collections.

Rational design, synthesis, pharmacophore modeling, and docking studies for identification of novel potent DNA-PK inhibitors

Drugs of cancer based upon ionizing radiation or chemotherapeutic treatment may affect breaking of DNA double strand in cell. DNA-PK enzyme has emerged as an attractive target for drug discovery efforts toward DNA repair pathways. Hence, the search for potent and selective DNA-PK inhibitors has particularly considered state-of-the art and several series of inhibitors have been designed. In this article, a novel benchmark DNA-PK database of 43 compounds was built and described. Ligand-based approaches including pharmacophore and QSAR modeling were applied and novel models were introduced and analyzed for predicting activity test for DNA-PK drug candidates. Based upon the modeling results, we gave a report of synthesis of fifteen novel 2-((8-methyl-2-morpholino-4-oxo-4H-benzo[e][1,3]oxazin-7-yl)oxy)acetamide derivatives and in vitro evaluation for DNA-PK inhibitory and antiproliferative activities. These fifteen compounds overall are satisfied with Lipinskis rule of five. The biological testing of target compounds showed five promising active compounds 7c, 7d, 7f, 9e and 9f with micromolar DNA-PK activity range from 0.25 to 5µM. In addition, SAR of the compounds activity was investigated and confirmed that the terminal aryl moiety was found to be quite crucial for DNA-PK activity. Moreover flexible docking simulation was done for the potent compounds into the putative binding site of the 3D homology model of DNA-PK enzyme and the probable interaction model between DNA-PK and the ligands was investigated and interpreted.

Molecular properties prediction, synthesis, and diuretic activity of phenoxy acetic acid bearing pyrazolines

A new series of phenoxyacetic acid bearing pyrazoline derivatives 7a–k were synthesized and characterized by IR, 1H-NMR, and mass spectral data. The investigated compounds were screened for their diuretic activity by standard Lipschitz method. Furthermore, the series under investigation were assessed for their drug-likeness by suitable software programs. These compounds were found to have promising results against a given set of diuretic parameters, i.e., cumulative urine output, diuretic activity, diuretic action, and Lipchitz values. Nevertheless, compounds 7d, 7h, 7i, and 7k bearing electron withdrawing group (Cl−) showed pronounced diuretic propensity than the standard furosemide.

Design, Synthesis and Qualitative Structure Activity Relationship Evaluations of Quinoline-Based Bisarylimidazoles as Antibacterial Motifs

BACKGROUND The emergence of drug-resistant bacteria in clinical practice has propelled a concerted effort to find new classes of antibiotics that will circumvent current modes of resistance. We previously described a set of imidazopyridine antibacterial leads that contain a core composed of benzimidazole and a central phthalic acid linker. These compounds showed potent antibacterial properties against a wide range of Gram-positive and Gram-negative bacteria. In this respect, we conducted a systematic exploration of new disubstituted imidazole functionalities on quinoline 4-position as the central linker, to determine the factors that direct the potent antibacterial activity. We found that some of the newly synthesized compounds possessed more potent activity compared to currently available medications. The newly synthesized compounds were screened against several clinical isolates and Staphylococcus aureus, including the methicillinresistant (MRSA) and the methicillin-sensitive (MSAA). METHODS The goal of this work is to undertake rigorous testing of new hybrid scaffolds of quinoline flanked by diaryl imidazoles and their structure-activity against a range of bacterial strains. Described herein is the account of the modification of the central linker region, the imidazole functionality, and substituents at the 4-position of the quinoline, and their effect on the antibacterial potency of the resulting derivatives. Our efforts here have been driven by previous reports on the applications of Pfitzinger cyclization protocol. This complexity-generating reaction transforms a relatively simple substrate, into a more complex products with the potential for diversification via functionalization of the resultant acid. RESULTS We identified compounds that possess potent and broad-spectrum antibacterial activities against clinical isolates and drug resistant strains. Structure-Activity relationships of these compounds were further explored to determine the crucial structural features needed to enhance their antibacterial activity. In this respect, it was found that, hydrophobic and electron-withdrawing moieties, such as halogens, were required on each end of the isoquinoline-based bisaryl imidazole hybrid motifs to produce broad-spectrum activity against the tested strains. Thus, molecules containing halophenyl or pyridyl arms were found more potent than molecules containing thiophene and/or electron-releasing groups on the phenyl arms, which showed much less antibacterial activity against the tested strains. CONCLUSION In summary, 4-(4,5-diphenyl-1H-imidazol-2-yl)-2-phenylquinoline systems can be assembled efficiently through the Pfitzinger ring expansion- condensation strategy. This approach appears to hold considerable synthetic utility. The particular value of such a synthetic route resides on the conciseness and efficiency through which imidazo-quinoline construction can be synthesized from structurally simple and accessible acetophenone precursors.

Molecular docking and glucosidase inhibition studies of novel N-arylthiazole-2-amines and Ethyl 2-[aryl(thiazol-2-yl)amino]acetates

This study describes an efficient synthesis of a series of novel ethyl 2-[aryl(thiazol-2-yl)amino]acetates (4a–l) from N-arylthiazole-2-amines (3a–l). The reaction conditions were optimized and the best results were obtained when ethyl chloroacetate was used as alkylating agent and NaH as base in THF. α-glucosidase and β-glucosidase inhibition activities of N-arylthiazole-2-amines (3a–l) and ethyl 2-[aryl(thiazol-2-yl)amino]acetates (4a–l) were determined, which revealed that most of the compounds showed high percentage inhibition towards the enzymes. Among the synthesized compounds, 4e appeared to have the highest inhibition towards α-glucosidase having IC50 value of 150.4 ± 1.9 μM which was almost two folds as compared to acarbose (336.9 ± 9.0 μM) taken as standard. Molecular docking of the compounds 3g, 3f, 4a, and 4e was also performed which showed their bonding modes to the enzyme’s active sites via amino and acetate groups, respectively.

Bis-(5-substituted-2-thiono-1,3,5-thiadiazinan-3-yl) butane as a scaffold of anti-proliferative activity, blended by a multicomponent process

AbstractIn the search for promising anti-proliferative agents that might be helpful in the treatment of cancer effectively, several compounds in a series (4b–j) comprising 1,4-bis (5-substituted -2-thiono-2H-tetrahydro-1,3,5-thiadiazin-3-yl) butane derivatives have been isolated. The aimed two privileged thiadiazinane pharmacophores were symmetrically assembled in one molecular frame via 1,4-diaminobutane; the endogenous compound produced by the breakdown of some amino acids that’s known as putrescine. The thiadiazinane rings bearing variable substituents at N-5 as well. The structure of the new derivatives, which were obtained by domino-reactions in water are confirmed by NMR and ESI-MS spectra. Data of 1H-NMR and 13C-NMR. NMR-spectra revealed symmetrical structural features. The anti-proliferative activity was evaluated against five different human cancer cell lines. Compounds 4b, 4d, 4e, and 4j (IC50 range 0.11–0.24 µM), were found potent against Hep3B (hepatocellular carcinoma). Compounds 4d and 4e are also potent (IC50 = 0.42 and 0.41 µM) against U-87 MG (Brain (glioblastoma astrocytoma)). Moreover, 4d provided (IC50 = 0.53 µM) against HepG2 (hepatocellular carcinoma), (A549 (lung carcinoma), and HT-29 (human colorectal adenocarcinoma), as well as normal cell line (fibroblast F180). All the derivatives 4b, 4d, 4e, and 4j are not only more potent, but also relatively safer than doxorubicin in the cell-lines mentioned. The anti-proliferative profile indicates that these compounds are good leads as anti-cancer agents and merit further studies to optimize their structure, detect their bio-targets and in vivo activity. New butane-bis-thiadiazinanes 4e, 4d, 4j, and 4b were found potent against Hep3B (hepatocellular carcinoma) providing (IC50 of 0.11, 0.21, 0.21, and 0.24 µM, respectively) and of high safety index (SI), compared to doxorubicin.

Inhibition of SHP2 by new compounds induces differential effects on RAS/RAF/ERK and PI3K/AKT pathways in different cancer cell types

SummaryKinases and phosphatases are important players in growth signaling and are involved in cancer development. For development of targeted cancer therapy, attention is given to kinases rather than phosphatases inhibitors. Src homology region 2 domain-containing protein tyrosine phosphatase2 (SHP2) is overexpressed in different types of cancers. We investigated the SHP2-inhibitory effects of two new 5-aminosalicylate–4-thiazolinones in human cervical (HeLa) and breast (MCF-7 & MDA-MB-231) cancer cells. In-silico molecular docking showed preferential affinity of the two compounds towards the catalytic over the allosteric site of SHP2. An enzymatic assay confirmed the docking results whereby 0.01 μM of both compounds reduced SHP2 activity to 50%. On cellular level, the two compounds significantly reduced the expression of SHP2, KRAS, p-ERK and p-STAT3 in HeLa but not in the other two cell lines. Phosphorylation of AKT and JNK was enhanced in HeLa and MCF7. Both compounds exhibited anti-proliferative/anti-migratory effects on HeLa and MCF7 but not in MDA-MB-231 cells. These results indicate that inhibition of SHP2 and its downstream pathways by the two compounds might be a promising strategy for cancer therapy in some but not all cancer types.

An Efficient Synthesis of bi‐Aryl Pyrimidine Heterocycles: Potential New Drug Candidates to Treat Alzheimer's Disease

A series of 13 novel pyrimidine‐based sulfonamides 6a–m were synthesized in short periods of time under microwave conditions in good to excellent yield (54–86%). The chemical structures of these heterocycles consist of a central pyrimidine ring having a phenyl group and pyrimidine groups with sulfonamide motifs. The enzyme inhibitory potential of these compounds was investigated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) because these enzymes play a crucial role in the treatment of Alzheimers disease. As compared to the reference compound eserine (IC50 = 0.04 ± 0.0001 μM for AChE and IC50 = 0.85 ± 0.0001 μM for BChE), the IC50 values of the synthesized compounds ranged from 3.73 ± 0.61 μM to 57.36 ± 0.22 μM for AChE and 4.81 ± 0.16 μM to 111.61 ± 0.53 μM for BChE. Among these tested compounds, 6j having a −CH3 group was found to be the most potent one against both enzymes (AChE, IC50 = 3.73 ± 0.61 μM; BChE, IC50 = 4.81 ± 0.16 μM). Quantitative structure–activity relationship (QSAR) and molecular docking studies of the synthesized compounds were also performed.

Peptide Derivatives of 1,2-Dihydro-3-Methyl-2-Oxoquinoxaline-6-Carboxylic Acid: Synthesis and Evaluation of Antimicrobial, Antifungal and Antiviral Potential

1,2-dihydro-3-methyl-2-oxoquinoxaline-6-carboxylic acid (S1) was prepared and coupled with various amino acid tri/tetrapeptide methyl esters to afford new quinoxalopeptide derivatives (S1a – S1i). The synthesized derivatives were characterized and screened for their antibacterial, antifungal and anthelmintic activity. Furthermore, molecular docking study revealed their potential in targeting human papillomavirus (HPV-16) E6 oncoprotein.