Identification of small-molecule urea derivatives as novel NAMPT inhibitors via pharmacophore-based virtual screening

Ozgencil, Fikriye
Atalay, Rengül
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-prophosphate (PRPP) to yield nicotinamide mononucleotide (NMN), a rate limiting enzyme in a mammalian salvage pathway of nicotinamide adenine dinucleotide (NAD(+)) synthesis. Recently, intracellular NAD(+) has received substantial attention due to the recent discovery that several enzymes including poly(ADPribose) polymerases (PARPs), mono(ADP-ribose) transferases (ARTs), and sirtuins (SIRTs), use NAD(+) as a substrate, suggesting that intracellular NAD(+) level may regulate cytokine production, metabolism, and aging through these enzymes. NAMPT is found to be upregulated in various types of cancer, and given its importance in the NAD(+) salvage pathway, NAMPT is considered as an attractive target for the development of new cancer therapies. In this study, the reported NAMPT inhibitors bearing amide, cyanoguanidine, and urea scaffolds were used to generate pharmacophore models and pharmacophore-based virtual screening studies were performed against ZINC database. Following the filtering steps, ten hits were identified and evaluated for their in vitro NAMPT inhibitory effects. Compounds GF4 (NAMPT IC50 = 2.15 +/- 0.22 mu M) and GF8 (NAMPT IC50 = 7.31 +/- 1.59 mu M) were identified as new urea-typed inhibitors of NAMPT which also displayed cytotoxic activities against human HepG2 hepatocellular carcinoma cell line with IC50 values of 15.20 +/- 1.28 and 24.28 +/- 6.74 mu M, respectively.


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The coupling of ferrocenyl alkynes with cyclopropylcarbene-chromium complex leads to ferrocenyl-substituted 2-cyclopentenones with or without a hydroxy substituent, namely 4-cyclopentene-1,3-diones, 2-cyclobutenones, and alpha, beta-unsaturated aldehydes in varying amounts. The reaction initially produces a cyclopentadienone intermediate, then to the double bond of which, bearing a ferrocenyl group, addition of water occurs to afford hydroxy-substituted 2-cyclopentenones. In all the products, the hydroxy gr...
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Citation Formats
F. Ozgencil, G. EREN, Y. ÖZKAN, S. GÜNTEKİN ERGÜN, and R. Atalay, “Identification of small-molecule urea derivatives as novel NAMPT inhibitors via pharmacophore-based virtual screening,” BIOORGANIC & MEDICINAL CHEMISTRY, pp. 0–0, 2020, Accessed: 00, 2020. [Online]. Available: