103740-34-7Relevant articles and documents
Pharmacological characterization of a new series of carbamoylguanidines reveals potent agonism at the H2R and D3R
Biselli, Sabrina,Bresinsky, Merlin,Buschauer, Armin,Forster, Lisa,Honisch, Claudia,Pockes, Steffen,Tropmann, Katharina,Bernhardt, Günther
, (2021/02/12)
Even today, the role of the histamine H2 receptor (H2R) in the central nervous system (CNS) is widely unknown. In previous research, many dimeric, high-affinity and subtype-selective carbamoylguanidine-type ligands such as UR-NK22 (5, pKi = 8.07) were reported as H2R agonists. However, their applicability to the study of the H2R in the CNS is compromised by their molecular and pharmacokinetic properties, such as high molecular weight and, consequently, a limited bioavailability. To address the need for more drug-like H2R agonists with high affinity, we synthesized a series of monomeric (thio)carbamoylguanidine-type ligands containing various spacers and side-chain moieties. This structural simplification resulted in potent (partial) agonists (guinea pig right atrium, [35S]GTPγS and β-arrestin2 recruitment assays) with human (h) H2R affinities in the one-digit nanomolar range (pKi (139, UR-KAT523): 8.35; pKi (157, UR-MB-69): 8.69). Most of the compounds presented here exhibited an excellent selectivity profile towards the hH2R, e.g. 157 being at least 3800-fold selective within the histamine receptor family. The structural similarities of our monomeric ligands to pramipexole (6), a dopamine receptor agonist, suggested an investigation of the binding behavior at those receptors. The target compounds were (partial) agonists with moderate affinity at the hD2longR and agonists with high affinity at the hD3R (e.g. pKi (139, UR-KAT523): 7.80; pKi (157, UR-MB-69): 8.06). In summary, we developed a series of novel, more drug-like H2R and D3R agonists for the application in recombinant systems in which either the H2R or the D3R is solely expressed. Furthermore, our ligands are promising lead compounds in the development of selective H2R agonists for future in vivo studies or experiments utilizing primary tissue to unravel the role and function of the H2R in the CNS.
Design, synthesis and molecular modelling studies of 1-methyl-3-(4-substituted phenyl-1,3thiazol-2-yl)-2-(pyridin-3-yl)-2,3-dihydroquinazolin-4(1h)-ones as potent anticancer agents
Nagaladinne, Nizamuddin,Hindustan, Abdul Ahad,Nayakanti, Devanna
, p. 3067 - 3074 (2021/01/06)
The present study involves the design, synthesis, characterization and molecular docking studies of biologically active quinazolin-4-ones, which were synthesized by condensing 2-amino-4-substituted phenylthiazole with N-methylbenzoxazin-4-one. The N-methylbenzoxazin-4-one and 2-amino-4-substituted phenylthiazole were synthesized from N-methylanthranilic acid and substituted ketones, respectively. The ADME properties determined the synthetic accessibility of quinazolin-4-ones by in silico Swiss ADME. The colorectal anticancer screening was done by using cell HT-29 human colorectal adenocarcinoma based on molecular docking studies on 3GC7-the structure of p38alpha in complex with dihydroquinazolinone. Finally, compounds 5Dh8, 5DF6, 5Db2 and 5Di9 exhibited better activity at a concentration 10 μg/mL when compared to 5-fluorouracil. The ADME properties revealed that all the compounds were within the range and docking studies showed the highest binding with glide score -7.19 and -7.027 Kcal/mol compared to the target protein -10.67 Kcal/mol.
Identification of novel 2-aminothiazole conjugated nitrofuran as antitubercular and antibacterial agents
Ran, Kai,Gao, Chao,Deng, Hongxia,Lei, Qian,You, Xinyu,Wang, Ningyu,Shi, Yaojie,Liu, Zhihao,Wei, Wei,Peng, Cuiting,Xiong, Lu,Xiao, Kunjie,Yu, Luoting
supporting information, p. 3669 - 3674 (2016/07/21)
The emergence of antibiotic resistant pathogens is an ongoing main problem in the therapy of bacterial infections. In order to develop promising antitubercular and antibacterial lead compounds, we designed and synthesized a new series of derivatives of 2-aminothiazole conjugated nitrofuran with activities against both Mycobacterium tuberculosis and Staphylococcus aureus. Eight compounds 12e, 12k, 12l, 12m, 18a, 18d, 18e, and 18j emerged as promising antitubercular agents. Structure–activity relationships (SARs) were discussed and showed that the derivatives substituted at the position-3 of benzene of 5-nitro-N-(4-phenylthiazol-2-yl)furan-2-carboxamide exhibited superior potency. The most potent compound 18e, substituted with benzamide at this position, displayed minimum inhibitory concentrations (MICs) of 0.27 μg/mL against Mtb H37Ra and 1.36 μg/mL against S. aureus. Furthermore, compound 18e had no obvious cytotoxicity to normal Vero cells (IC50= 50.2 μM). The results suggest that the novel scaffolds of aminothiazole conjugated nitrofuran would be a promising class of potent antitubercular and antimicrobial agents.