2295-58-1Relevant academic research and scientific papers
Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor
Ng, Chean Hui,Rullah, Kamal,Mohd. Aluwi, Mohd. Fadhlizil Fasihi,Abas, Faridah,Lam, Kok Wai,Ismail, Intan Safinar,Narayanaswamy, Radhakrishnan,Jamaludin, Fadzureena,Shaari, Khozirah
, p. 11645 - 11659 (2014)
The natural product molecule 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) isolated from the medicinal plant Melicope ptelefolia was shown to exhibit potent lipoxygenase (LOX) inhibitory activity. It is known that LOX plays an important role in inflammatory response as it catalyzes the oxidation of unsaturated fatty acids, such as linoleic acid to form hydroperoxides. The search for selective LOX inhibitors may provide new therapeutic approach for inflammatory diseases. Herein, we report the synthesis of tHGA analogs using simple Friedel-Craft acylation and alkylation reactions with the aim of obtaining a better insight into the structure-activity relationships of the compounds. All the synthesized analogs showed potent soybean 15-LOX inhibitory activity in a dose-dependent manner (IC50 = 10.31-27.61 μM) where compound 3e was two-fold more active than tHGA. Molecular docking was then applied to reveal the important binding interactions of compound 3e in soybean 15-LOX binding site. The findings suggest that the presence of longer acyl bearing aliphatic chain (5Cs) and aromatic groups could significantly affect the enzymatic activity.
A test for homology: Photoactive crystalline assemblies involving linear templates based on a homologous series of phloroglucinols
Friscic, Tomislav,Drab, David M.,MacGillivray, Leonard R.
, p. 4647 - 4650 (2004)
(Chemical Equation Presented) Cocrystallization of trans-1,2-bis(4-pyridyl) ethylene (4,4′-bpe) with eight members of a homologous series of phloroglucinols 1a-h yields molecular solids 2(1a-h)·2(4,4′-bpe) with components held together by four O-H...N hydrogen bonds. In each case, the molecules assemble to form a discrete four-component assembly with olefins preorganized for a [2 + 2] photodimerization. UV irradiation of each member in the series of solids produces rctt-tetrakis(4-pyridyl)cyclobutane (4,4′-tpcb), stereospecifically, in up to 100% yield.
Development of a novel nitric oxide (NO) production inhibitor with potential therapeutic effect on chronic inflammation
Chen, Lijuan,Fan, Tiantian,Lei, Xiangui,Teichmann, Alexander Tobias,Wang, Amu,Wang, Chao,Wei, Zhe,Wieland, Frank Heinrich,Yang, Youzhe,Yin, Jinxiang,Zhou, Li,Zhu, Yue
, (2020/03/24)
Inflammation is a complex biological response to stimuli. Activated macrophages induced excessively release of pro-inflammatory cytokines and mediators such as endogenous radical nitric oxide (NO) play a significant role in the progression of multiple inflammatory diseases. Both natural and synthetic chalcones possess a wide range of bioactivities. In this work, thirty-nine chalcones and three related compounds, including several novel ones, based on bioactive kava chalcones were designed, synthesized and their inhibitory effects on NO production in RAW 264.7 cells were evaluated. The novel compound (E)-1-(2′-hydroxy-4′,6′-dimethoxyphenyl)-3-(3-methoxy-4-(3-morpholinopropoxy)phenyl)prop-2-en-1-one (53) exhibited a better inhibitory activity (84.0%) on NO production at 10 μM (IC50 = 6.4 μM) with the lowest cytotoxicity (IC50 > 80 μM) among the tested compounds. Besides, western blot analysis indicated that compound 53 was a potent down-regulator of inducible nitric oxide synthase (iNOS) protein. Docking study revealed that compound 53 also can dock into the active site of iNOS. Furthermore, at the dose of 10 mg/kg/day, compound 53 could both significantly suppress the progression of inflammation on collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models. In addition, the structure-activity relationship (SAR) of the kava chalcones based analogs was also depicted.
Design, synthesis and biological evaluation of chalcones as reversers of P-glycoprotein-mediated multidrug resistance
Yin, Huanhuan,Dong, Jingjing,Cai, Yingchun,Shi, Ximeng,Wang, Hao,Liu, Guixia,Tang, Yun,Liu, Jianwen,Ma, Lei
, p. 350 - 366 (2019/07/19)
Overexpression of P-glycoprotein (P-gp) is one of the major causes for multidrug resistance (MDR), which has become a major obstacle in cancer therapy. One hopeful approach to reverse the MDR is to develop inhibitors of P-gp in expression and/or function. Here, we designed and synthesized a series of chalcone derivatives as P-gp inhibitors and evaluated their potential reversal activities against MDR. Among them, the most active compound MY3 had little intrinsic cytotoxicity and showed the highest activity (RF = 50.19) in reversing DOX resistance in MCF-7/DOX cells. Further studies demonstrated that MY3 could increase intracellular accumulation of DOX and inhibit expression of P-gp at mRNA and protein levels. More importantly, MY3 significantly enhanced the efficacy of DOX against the tumor xenografts bearing MCF-7/DOX cells with the precondition of unchanged body weight. Therefore, MY3 might represent a promising lead to develop MDR reversal agents for cancer chemotherapy.
Synthesis and antibiotic activity of novel acylated phloroglucinol compounds against methicillin-resistant Staphylococcus aureus
Mittal, Navriti,Tesfu, Haben H.,Hogan, Andrew M.,Cardona, Silvia T.,Sorensen, John L.
, p. 253 - 259 (2019/02/19)
The rise in antibiotic resistance among pathogenic microorganisms has created an imbalance in the drugs available for treatment, in part due to the slow development of new antibiotics. Cystic fibrosis (CF) patients are highly susceptible to antibiotic-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Phloroglucinols and related polyketide natural products have demonstrated antimicrobial activity against a number of Gram-positive bacteria including S. aureus. In this study, we investigated a series of acylated phloroglucinol derivatives to determine their potential as lead compounds for the design of novel therapeutics. To assess the activity of these compounds, we determined the minimum inhibitory and bactericidal concentration (MIC and MBC, respectively), the minimum biofilm inhibitory and biofilm eradication concentration (MBIC and MBEC, respectively), and evaluated hemolytic activity, as well as their interaction with clinically relevant antibiotics. Of the 12 compounds tested against MRSA and methicillin-susceptible strains, four showed MIC values ranging from 0.125 to 8 μg ml?1 and all of them were bactericidal. However, none of the compounds were able to eradicate biofilms at the concentrations tested. Three of the four did not display hemolytic activity under the conditions tested. Further studies on the interactions of these compounds with clinically relevant antibiotics showed that phlorodipropanophenone displayed synergistic activity when paired with doxycycline. Our results suggest that these acylated phloroglucinols have potential for being further investigated as antibacterial leads.
Total synthesis of acylphloroglucinols and their antibacterial activities against clinical isolates of multi-drug resistant (MDR) and methicillin-resistant strains of Staphylococcus aureus
Rahman, M. Mukhlesur,Shiu, Winnie K.P.,Gibbons, Simon,Malkinson, John P.
supporting information, p. 255 - 262 (2018/06/20)
Bioassay-directed drug discovery efforts focusing on various species of the genus Hypericum led to the discovery of a number of new acylphloroglucinols including (S,E)-1-(2-((3,7-dimethylocta-2,6-dien-1-yl)oxy)-4,6-dihydroxyphenyl)-2-methylbutan-1-one (6, olympicin A) from H. olympicum, with MICs ranging from 0.5 to 1 mg/L against a series of clinical isolates of multi-drug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA) strains. The promising activity and interesting chemistry of olympicin A prompted us to carry out the total synthesis of 6 and a series of analogues in order to assess their structure-activity profile as a new group of antibacterial agents. Following the synthesis of 6 and structurally-related acylphloroglucinols 7–15 and 18–24, their antibacterial activities against a panel of S. aureus strains were evaluated. The presence of an alkyloxy group consisting of 8–10 carbon atoms ortho to a five-carbon acyl substituent on the phloroglucinol core are important structural features for promising anti-staphylococcal activity.
Hits-to-lead optimization of the natural compound 2,4,6-trihydroxy-3-geranyl-acetophenone (thga) as a potent lox inhibitor: Synthesis, structure-activity relationship (sar) study, and computational assignment
Ng, Chean Hui,Rullah, Kamal,Abas, Faridah,Lam, Kok Wai,Ismail, Intan Safinar,Jamaludin, Fadzureena,Shaari, Khozirah
, (2018/10/15)
A new series of 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) analogues were synthesized and evaluated for their lipoxygenase (LOX) inhibitory activity. Prenylated analogues 4a-g (half maximal inhibitory concentration (IC50) values ranging from 35 μM to 95 μM) did not exhibit better inhibitory activity than tHGA (3a) (IC50 value: 23.6 μM) due to the reduction in hydrophobic interaction when the alkyl chain length was reduced. One geranylated analogue, 3d, with an IC50 value of 15.3 μM, exhibited better LOX inhibitory activity when compared to tHGA (3a), which was in agreement with our previous findings. Kinetics study showed that the most active analogue (3e) and tHGA (3a) acted as competitive inhibitors. The combination of in silico approaches of molecular docking and molecular dynamic simulation revealed that the lipophilic nature of these analogues further enhanced the LOX inhibitory activity. Based on absorption, distribution, metabolism, excretion, and toxicity (ADMET) and toxicity prediction by komputer assisted technology (TOPKAT) analyses, all geranylated analogues (3a-g) showed no hepatotoxicity effect and were biodegradable, which indicated that they could be potentially safe drugs for treating inflammation.
Structural optimization and antibacterial evaluation of rhodomyrtosone B analogues against MRSA strains
Zhao, Liyun,Liu, Hongxin,Huo, Luqiong,Wang, Miaomiao,Yang, Bao,Zhang, Weimin,Xu, Zhifang,Tan, Haibo,Qiu, Sheng-Xiang
supporting information, p. 1698 - 1707 (2018/10/26)
Methicillin-resistant Staphylococcus aureus (MRSA) infections are well-known as a significant global health challenge. In this study, twenty-two congeners of the natural antibiotic rhodomyrtosone B (RDSB) were synthesized with the aim of specifically enhancing the structural diversity through modifying the pendant acyl moiety. The structure-activity relationship study against various MRSA strains revealed that a suitable hydrophobic acyl tail in the phloroglucinol scaffold is a prerequisite for antibacterial activity. Notably, RDSB analogue 11k was identified as a promising lead compound with significant in vitro and in vivo antibacterial activities against a panel of hospital mortality-relevant MRSA strains. Moreover, compound 11k possessed other potent advantages, including breadth of the antibacterial spectrum, rapidity of bactericidal action, and excellent membrane selectivity. The mode of action study of compound 11k at the biophysical and morphology levels disclosed that 11k exerted its MRSA bactericidal action by membrane superpolarization resulting in cell lysis and membrane disruption. Collectively, the presented results indicate that the novel modified RDSB analogue 11k warrants further exploration as a promising candidate for the treatment of MRSA infections.
Closed-loop myrtle ketone analogue and application thereof to antibacterial medicament
-
Paragraph 0024; 0026; 0029; 0030, (2018/12/02)
The invention discloses a closed-loop myrtle ketone analogue and application thereof to an antibacterial medicament. The structure of the closed-loop myrtle ketone analogue or a pharmaceutically-acceptable salt thereof is shown as a formula (1), wherein R is H, or a linear chain containing 1 to 15 carbon atoms, a branched chain, naphthenic base or an aryl group containing a benzene ring. The closed-loop myrtle ketone analogue can remarkably resist the bacteria of Vancomycin-resistant Enterococcus faecium (VRE), Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, Bacilluscereus, Propionibacterium acnes, Enterococcuse faecalis or Staphylococcus epidermidis, has anti-bacterial activity equivalent to that of vancomycin which is regarded as the last barrier of anti-bacterial medicaments, and can kill the VRE which is out of control of the vancomycin. As proved by further research on the action mechanism of the closed-loop myrtle ketone analogue as well as investigation in biophysics and morphological researches, 11k can sterilize an MRSA bacterial strain through membrane hyperpolarization in order to induce the breaking of the membrane, which represents a very beneficial sterilizing mechanism. The formula (1) is shown in the description.
Structure-activity relationships and optimization of acyclic acylphloroglucinol analogues as novel antimicrobial agents
Tan, Haibo,Liu, Hongxin,Zhao, Liyun,Yuan, Yao,Li, Bailin,Jiang, Yueming,Gong, Liang,Qiu, Shengxiang
supporting information, p. 492 - 499 (2016/10/04)
Methicillin-resistant Staphylococcus aureus (MRSA) poses a serious threat to global public health, because it exhibits resistance to existing antibiotics and therefore high rates of morbidity and mortality. In this study, twenty-one natural product-based acylphloroglucinol congeners were synthesized, which possessed different side chains. Antibacterial screening against MRSA strains revealed that acyl moiety tailoring is a prerequisite for the antibacterial activity. Moreover, the lipophilicity, rather than the magnitude of the hydrophobic acyl tail dominates variability in activity potency. Compound 11j was identified as a promising lead for the generation of new anti-MRSA drug development. It was discovered by optimization of the side chain length in light of the potency, the breadth of the antibacterial spectrum, the rate of bactericidal action, as well as the membrane selectivity. Compound 11j exerted profound in?vitro antibacterial activity against the MRSA strain (JCSC 2172), and its MIC was 3-4 orders of magnitude lower than that of vancomycin. A preliminary mode of action study of compound 11j at the biophysical and morphology levels disclosed that the mechanism underlying its anti-MRSA activity included membrane depolarization and, to a lesser extent, membrane disruption and cell lysis.
