- Discovery of 1,3,4-oxadiazol-2-one-containing benzamide derivatives targeting FtsZ as highly potent agents of killing a variety of MDR bacteria strains
-
The spread of infections caused by multidrug-resistant (MDR) pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), has created a need for new antibiotics with novel mechanisms of action. The bacterial division protein FtsZ has been identified as a novel drug target that can be exploited clinically. As part of an ongoing effort to develop FtsZ-targeting antibacterial agents, we describe herein the design, synthesis and bioactivity of six series of novel 1,3,4-oxadiazol-2-one-containing, 1,2,4-triazol-3-one-containing and pyrazolin-5-one-containing benzamide derivatives. Among them, compound A14 was found to be the most potent antibacterial agent, much better than clinical drugs such as ciprofloxacin, linezolid and erythromycin against all the tested gram-positive strains, particularly methicillin-resistant, penicillin-resistant and clinical isolated S. aureus. Subsequent studies on biological activities and docking analyses proved that A14 functioned as an effective compound targeting FtsZ. Preliminary SAR indicated a general direction for further optimization of these novel analogues. Taken together, this research provides a promising chemotype for developing newer FtsZ-targeting bactericidal agents.
- Bi, Fangchao,Song, Di,Qin, Yinhui,Liu, Xingbang,Teng, Yuetai,Zhang, Na,Zhang, Panpan,Zhang, Nan,Ma, Shutao
-
p. 3179 - 3193
(2019/06/17)
-
- Synthesis of Aryl Hydrazines via CuI/BMPO Catalyzed Cross-Coupling of Aryl Halides with Hydrazine Hydrate in Water
-
The N,N’-bis(2,6-dimethylphenyl)oxalamide was discovered as a powerful ligand for Cu-catalyzed cross-coupling of aryl halides with hydrazine hydrate, leading to the formation of a variety of aryl hydrazines at 80 oC in water under the assistance of K3PO4 and 4 mol% cetyltrimethylammonium bromide from aryl bromides and aryl iodides. Good to excellent yields were observed in most cases.
- Kumar, Siripuram Vijay,Ma, Dawei
-
supporting information
p. 1003 - 1006
(2018/09/20)
-
- Synthesis, in vitro Antimicrobial, and Cytotoxic Activities of New 1,3,4-Oxadiazin-5(6H)-one Derivatives from Dehydroabietic Acid
-
A series of new 1,3,4-oxadiazin-5(6H)-one derivatives (6a–n) of dehydroabietic acid were designed and synthesized as potential antimicrobial and antitumor agents. Their structures were characterized by IR, 1H NMR, 13C NMR, MS, and elemental analyses. All the title compounds were evaluated for their antimicrobial activity against four bacterial and three fungal strains using the serial dilution method. Among them, compound 6e showed the highest antibacterial activity against Bacillus subtilis with a minimum inhibitory concentration (MIC) value of 1.9 μg/mL. In addition, the in vitro cytotoxic activities of the title compounds were also assayed against three human carcinoma cell lines (MCF-7, SMMC-7721, and HeLa) through the MTT colorimetric method. As a result, compounds 6b, 6g, 6k, and 6m exhibited significant inhibition against at least one cell line with IC50 values below 10 μM. Compound 6m was especially found to be the most potent derivative with IC50 values of 2.26 ± 0.23, 0.97 ± 0.11, and 1.89 ± 0.31 μM against MCF-7, SMMC-7721, and HeLa cells, respectively, comparable to positive control etoposide.
- Jin, Xiao-Yan,Zhang, Kang-Ping,Chen, Hao,Miao, Ting-Ting,Wang, Shi-Fa,Gu, Wen
-
p. 538 - 547
(2018/06/11)
-
- Synthesis and biological evaluation of (1-aryl-1H-pyrazol-4-yl) (3,4,5-trimethoxyphenyl)methanone derivatives as tubulin inhibitors
-
A series of (1-aryl-1H-pyrazol-4-yl) (3,4,5-trimethoxyphenyl)methanones (8a-p, 9a-p) and ketoxime (10c) derivatives were designed and synthesized as antitubulin agents. All of the target compounds were evaluated for the in vitro anti-proliferative activities against three tumor cell lines (A549, HT-1080, SGC-7901). The most promising compounds in this class were (1-(p-tolyl)-1H-pyrazol-4-yl) (3,4,5-trimethoxyphenyl)methanone (9c) and its ketoxime derivative (10c), which significantly inhibited tumor cells growth with IC50 value of 0.054–0.16 μM. Meanwhile, compound 9c exhibited effectively inhibitory activity of tubulin polymerization. Consistent with its antitubulin activity, compound 9c could destructively damage microtubule network and arrest SGC-7901 cell cycle at G2/M phase significantly. The structure-activity relationship (SAR) and conformational analysis indicate that methyl group at C4-position of C-ring is critical for the activities and the amino group at the C5-position of B-ring plays a negative role in maintaining bioactivity. Furthermore, a molecular docking study was performed to elucidate its binding mode at the colchicine site in the tubulin heterodimer.
- Zhai, Min'an,Wang, Long,Liu, Shiyuan,Wang, Lijing,Yan, Peng,Wang, Junfang,Zhang, Jingbo,Guo, Haifei,Guan, Qi,Bao, Kai,Wu, Yingliang,Zhang, Weige
-
p. 137 - 147
(2018/07/13)
-
- Facile and convenient synthesis of aryl hydrazines via copper-catalyzed C-N cross-coupling of aryl halides and hydrazine hydrate
-
An efficient and convenient method for the synthesis of aryl hydrazines has been developed via copper-catalyzed cross-coupling of aryl bromides and hydrazine with a readily accessible ligand and water as a solvent. The multigram scale procedure is applicable to aryl bromides bearing both moderately electron-donating and electron-withdrawing substituents in the aromatic nucleus. No column chromatography is required to obtain aryl hydrazine hydrochlorides in good yields.
- Kurandina, Daria V.,Eliseenkov, Eugene V.,Ilyin, Petr V.,Boyarskiy, Vadim P.
-
p. 4043 - 4048
(2014/06/09)
-
- Novel triazole derivatives, process for their preparation and pharmaceutical compositions containing them
-
The invention relates to a compound of formula in which R1, X1, X2, X3, X4, R4, Y1, Y2 and Y3 are as defined in claim 1. These compounds are CCK-receptor agonists.
- -
-
-
- N-methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT(1D) receptor agonist
-
It has been observed that reported 5-HT(1D) receptor agonists have at least one heteroatom (N, O, or S) on the 5-substituent of the indole. This has led to the hypothesis that a 5-substituent capable of participating in hydrogen bonding is critical for conveying high affinity. This article describes the synthesis and biological evaluation of a new series of 5- alkyltryptamine analogues, which does not have a heteroatom in the 5- substituent group. In contrast to the hypothesis, 5-alkyltryptamines all exhibit high binding affinities for the human 5-HT(1D) receptor. The size of the lipophilic alkyl group at the 5-position of the indole has significant impact on the 5-HT(1D) binding affinity. Compounds with a tert-butyl group at the 5-position such as 9d, 10, and 11 were identified. These analogues display high binding affinity (K(i) 1 nM) and moderate receptor selectivity in comparison with known antimigraine agents such as sumatriptan, naratriptan, rizatriptan, and VML-251.
- Xu, Yao-Chang,Schaus, John M.,Walker, Clint,Krushinski, Joe,Adham, Nika,Zgombick, John M.,Liang, Sidney X.,Kohlman, Dan T.,Audia, James E.
-
p. 526 - 531
(2007/10/03)
-