Kamel Metwally

1,3,4-oxadiazole-2-thione Derivatives; Novel Approach for Anticancer and Tubulin Polymerization Inhibitory Activities

A series of novel 5-(substituted phenyl)-3-[(substituted phenylamino)methyl]-3H-[1,3,4]oxadiazole-2- thione derivatives were prepared and their in vitro cytotoxicity was evaluated against a panel of three cancer cell lines, namely, hepatocarcinoma HepG2, breast adenocarcinoma MCF-7, and leukemia HL-60 cells, using the widely accepted MTT assay. In general, the synthesized compounds displayed weak to moderate cytotoxic activity against the three tested cell lines. Compound 5a, which has trimethoxy substituents on both phenyl rings, exhibited the highest cytotoxic effect against all cell lines tested with IC50 values of 12.01, 7.52 and 9.7 μM against HepG2, MCF-7 and HL-60 cells, respectively. Mechanistic studies revealed that the test compounds showed a good inhibitory effect on cellular tubulin of hepatocellular carcinoma. Compound 5h was the most potent tubulin inhibitor in HepG2 cells, with 81.1 % inhibition of the original control tubulin. Moreover, the mechanism of tubulin polymerization inhibition was confirmed by immunofluorescence assay, flow cytometry, and docking study.

The antimitotic pyrimido[4,5-c]quinolin-1(2H)-one scaffold: probing substituents at position 3

As a continuation of our efforts to optimize the antimitotic effect of our pyrimido[4,5-c]quinolin-1(2H)-one scaffold, we were interested in exploring the SAR of substituents at position 3 of this fused ring system. Target compounds 2a–r having substituents with diverse electronic and steric characteristics at the 3-phenyl ring were synthesized and tested for in vitro cytotoxicity against lung fibrosarcoma HT-1080 and colon adenocarcinoma HT-29 human cancer cell lines using the widely accepted MTT assay. Most of the compounds displayed cytotoxic effects in the low micromolar range. Clear-cut SAR conclusions were drawn from the available biological data. Generally, o-substitution results in a marked decrease or complete loss of cytotoxicity. Multimethoxy substitution in this particular position does not contribute to the cytotoxic effect but leads to cytotoxic selectivity for HT-1080 versus HT-29 cells. Interestingly, the best position for cytotoxicity of a halogen was the p-position, whereas m-substitution was the most favourable within the methyl/methoxy series. To confirm the mechanism of action previously identified for our closely related analogues, the most cytotoxic compounds were evaluated for their effects on cell cycle progression and tubulin polymerization. All compounds tested were found to arrest HT-1080 cells in the G2/M phase of the cell cycle and inhibit tubulin polymerization in a similar fashion to colcemid which is a known tubulin polymerization inhibitor.Graphical Abstract

Targeting methionyl tRNA synthetase: design, synthesis and antibacterial activity against Clostridium difficile of novel 3-biaryl-N-benzylpropan-1-amine derivatives.

Abstract The synthesis of a series of benzimidazole-N-benzylpropan-1-amines and adenine-N-benzylpropan-1-amines is described. Subsequent evaluation against two strains of the anaerobic bacterium Clostridium difficile was performed with three amine derivatives displaying MIC values of 16 μg/mL. Molecular docking studies of the described amines determined that the amines interact within two active site pockets of C. difficile methionyl tRNA synthetase with methoxy substituents in the benzyl ring and an adenine biaryl moiety resulting in optimal binding interactions.

Quinazolinone-based rhodanine-3-acetic acids as potent aldose reductase inhibitors: Synthesis, functional evaluation and molecular modeling study

A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors.

Corrigendum to “Synthesis and biological activity of 2,5-diaryl-3-methylpyrimido[4,5-c]quinolin-1(2H)-one derivatives” [Bioorg. Med. Chem. 15 (2007) 2434–2440]

Please cite this article in press as: Metwally K., et al. Bioorg. Med. Chem. (2017), http://dx.doi.org/10.1016/j.bmc.2017.03.025 Kamel Metwally a,⇑, Omar Aly , Enayat Aly , Abhijit Banerjee , Rudravajhala Ravindra , Susan Bane d Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt Department of Medicinal Chemistry, Faculty of Pharmacy, Elminia University, Elminia, Egypt Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt Department of Chemistry, Binghamton University, Binghamton, NY, USA