10328-92-4Relevant articles and documents
One-Pot Total Synthesis of Evodiamine and Its Analogues through a Continuous Biscyclization Reaction
Wang, Zi-Xuan,Xiang, Jia-Chen,Wang, Miao,Ma, Jin-Tian,Wu, Yan-Dong,Wu, An-Xin
, p. 6380 - 6383 (2018)
The one-pot total synthesis of evodiamine and its analogues is achieved using a three-component reaction. Through continuous biscyclization, various readily available substrates with good functional group tolerance were easily incorporated into biologically active quinazolinocarboline backbones. The use of triethoxymethane as a cosolvent was crucial for this quick and straightforward transformation.
Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket
Zhang, Tianhua,Lai, Zengwei,Yuan, Suying,Huang, Yi-You,Dong, Guoqiang,Sheng, Chunquan,Ke, Hengming,Luo, Hai-Bin
, p. 9828 - 9837 (2020)
Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel allosteric pocket induced dramatic conformation changes in the H-loop with a maximum 24 ? movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.
Synthesis and antimicrobial activity of novel 4-Hydroxy-2-quinolone analogs
Khamkhenshorngphanuch, Thitiphong,Kulkraisri, Kittipat,Janjamratsaeng, Alongkorn,Plabutong, Napasawan,Thammahong, Arsa,Manadee, Kanitta,Na Pombejra, Sarisa,Khotavivattana, Tanatorn
, (2020)
Alkyl quinolone has been proven to be a privileged scaffold in the antimicrobial drug discovery pipeline. In this study, a series of new 4-hydroxy-2-quinolinone analogs containing a long alkyl side chain at C-3 and a broad range of substituents on the C-6 and C-7 positions were synthesized. The antibacterial and antifungal activities of these analogs against Staphylococcus aureus, Escherichia coli, and Aspergillus flavus were investigated. The structure-activity relationship study revealed that the length of the alkyl chain, as well as the type of substituent, has a dramatic impact on the antimicrobial activities. Particularly, the brominated analogs 3j with a nonyl side chain exhibited exceptional antifungal activities against A. flavus (half maximal inhibitory concentration (IC50) = 1.05 μg/mL), which surpassed that of the amphotericin B used as a positive control. The antibacterial activity against S. aureus, although not as potent, showed a similar trend to the antifungal activity. The data suggest that the 4-hydroxy-2-quinolone is a promising framework for the further development of new antimicrobial agents, especially for antifungal treatment.
A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis, anti-microbial evaluation and molecular docking studies
Banu, Saleha,Bollu, Rajitha,Naseema, Mohammad,Gomedhika, P. Mary,Nagarapu, Lingaiah,Sirisha,Kumar, C. Ganesh,Gundasw, Shravan Kumar
, p. 1166 - 1170 (2018)
A series of piperazinyl-1,2-dihydroquinoline carboxylates were synthesized by the reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylates with various piperazines and their structures were confirmed by 1H NMR, 13C NMR, IR and mass spectral analysis. All the synthesized compounds were screened for their in vitro antimicrobial activities. Further, the in silico molecular docking studies of the active compounds was performed to explore the binding interactions between piperazinyl-1,2-dihydroquinoline carboxylate derivatives and the active site of the Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCQ). The docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9b and 10c were identified as promising antimicrobial lead molecules. This study might provide insights to identify new drug candidates that target the S. aureus virulence factor, dehydrosqualene synthase.
One-step Synthesis for the Preparation of Quinoline Alkaloid Analogues
Zografos, Alexandros L.,Mitsos, Christos A.,Igglessi-Markopoulou, Olga
, p. 1953 - 1955 (1999)
(Matrix Presented) A new one-step methodology has been introduced for the synthesis of quinoline alkaloid analogues. The reaction is based on a modification of the Mukaiyama aldol condensation, making use of the high reactivity of lactones or anhrydrides. The reaction is general and allows for the construction of new hetero polycondenced molecules in a one-step synthesis.
Pd(ii)-Catalyzed [4 + 1 + 1] cycloaddition of simple: O -aminobenzoic acids, CO and amines: Direct and versatile synthesis of diverse N -substituted quinazoline-2,4(1 H,3 H)-diones
Ding, Qianqian,Fan, Xuesen,Wang, Jinjun,Yang, Jingyi,Zhang, Guisheng,Zhang, Xiaopeng
, p. 526 - 535 (2021/01/28)
The mild, efficient, and straightforward synthesis of pharmaceutically and biologically active N3-substituted and N1,N3-disubstituted quinazoline-2,4-(1H,3H)-diones from simple and readily available substrates has been a huge challenge. Described here is a Pd(ii)-catalyzed [4 + 1 + 1] modular synthesis of diverse quinazoline-2,4-(1H,3H)-diones through one-pot cascade reactions of cyclocondensation of o-(alkyl)aminobenzoic acids with CO, amidation of the intermediate isatoic anhydrides with amines, and unprecedented carbonylation of the resulting o-aminobenzamides with CO under 1 atm and 60 °C conditions. The chemoselective and versatile multicomponent reaction allows for the diversities of the products including N3-substituted and N1,N3-disubstituted products, and even makes the substituents on N1,N3 the same or different from each other, which cannot be achieved by most traditional synthetic strategies. This journal is
N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides bearing heteroaromatic rings as novel antibacterial agents: Design, synthesis, biological evaluation and target identification
Xue, Wenjie,Li, Xueyao,Ma, Guixing,Zhang, Hongmin,Chen, Ya,Kirchmair, Johannes,Xia, Jie,Wu, Song
, (2020/02/04)
Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 μg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25–1 μg/mL vs. 1–64 μg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6–155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.
