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Mohamed A Ismail,1,2 Reem K Arafa,3 Magdy M Youssef,1,2 Wael M El-Sayed1,4 1Departments of Chemistry and Biological Sciences, College of Science, King Faisal University, Hofuf, Saudi Arabia; 2Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt; 3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 4Department of Zoology, Faculty of Science, University of Ain Shams, Abbassia, Cairo, Egypt Abstract: A series of 15 monocationic bithiophenes and isosteres were prepared and subjected to in vitro antiproliferative screening using the full National Cancer Institute (NCI)-60 cell line panel, representing nine types of cancer. Among the nine types of cancer involved in a five-dose screen, non-small cell lung and breast cancer cell lines were the most responsive to the antiproliferative effect of the tested compounds, especially cell lines A549/ATCC, NCI-H322M, and NCI-H460, whereas compounds 1a, 1c, 1d, and 7 exhibited potent activity, with GI50 values (drug concentration that causes 50% inhibition of cell growth) from less than 10 nM to 102 nM. In addition, compounds 1c and 1d gave GI50 values of 73 nM and 79 nM, respectively, against the MDA-MB-468 breast cancer cell line. Structure–activity relationship findings indicated that the mononitriles were far less active than their corresponding monoamidines and, within the amidines series, the bioisosteric replacement of a thiophene ring by a furan led to a reduction in antiproliferative activity. Also, molecular manipulations, involving substitution on the phenyl ring, or its replacement by a pyridyl, or alteration of the position of the amidine group, led to significant alteration in antiproliferative activity. On the other hand, DNA studies demonstrated that these monoamidine bichalcophenes have promising ability to cleave the genomic DNA. These monoamidines show a wide range of DNA affinities, as judged from their DNA cleavage effect, which are remarkably sensitive to all kinds of structural modifications. Finally, the novel bichalcophenes were tested for their antioxidant property by the ABTS (2,2'-azino- bis(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt) assay, as well as lipid and nitric oxide scavenging techniques, and were found to exhibit good-to-potent antioxidant abilities. Keywords: bithiophenes, anticancer, DNA cleavage, antioxidant, Suzuki coupling, Stille coupling

Magdy M Youssef,1,2 Reem K Arafa,3,4 Mohamed A Ismail1,21Department of Chemistry, College of Science, King Faisal University, Hofuf, Saudi Arabia; 2Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, 3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, 4Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Cairo, EgyptAbstract: This research work deals with the design and synthesis of a series of substituted phenylfuranylnicotinamidines 4a–i. Facile preparation of the target compounds was achieved by Suzuki coupling-based synthesis of the nitrile precursors 3a–i, followed by their conversion to the corresponding nicotinamidines 4a–i utilizing LiN(TMS)2. The antimicrobial activities of the newly synthesized nicotinamidine derivatives were evaluated against the Gram-negative bacterial strains Escherichia coli and Pseudomonas aeruginosa as well as the Gram-positive bacterial strains Staphylococcus aureus and Bacillus megaterium. The minimum inhibitory concentration values of nicotinamidines against all tested microorganisms were in the range of 10–20 µM. In specific, compounds 4a and 4b showed excellent minimum inhibitory concentration values of 10 µM against Staphylococcus aureus bacterial strain and were similar to ampicillin as an antibacterial reference. On the other hand, selected nicotinamidine derivatives were biologically screened for their cytotoxic activities against a panel of 60 cell lines representing nine types of human cancer at a single high dose at National Cancer Institute, Bethesda, MD, USA. Nicotinamidines showing promising activities were further assessed in a five-dose screening assay to determine their compound concentration causing 50% growth inhibition of tested cell (GI50), compound concentration causing 100% growth inhibition of tested cell (TGI), and compound concentration causing 50% lethality of tested cell (LC50) values. Structure-activity relationship studies demonstrated that the activity of members of this series can be modulated from cytostatic to cytotoxic based on the substitution pattern/nature on the terminal phenyl ring. The most active compound was found to be 4e displaying a submicromolar GI50 value of 0.83 µM, with TGI and LC50 values of 2.51 and 100 µM, respectively. Finally, the possible underlying mechanism of action of this series of compounds was investigated by determining their nuclease-like DNA degradation ability in addition to their antioxidant power and all monocations proved to be effective in all assays.Keywords: substituted phenylfuranylnicotinamidines, Suzuki coupling, antiproliferative, antibacterial, antioxidant