Synthesis and in vitro evaluation of substituted aryl- and hetarylmethyl phosphonate and phosphate — UMP derivatives as potential glucosyltransferase inhibitors

2002 ◽  
Vol 80 (8) ◽  
pp. 973-982 ◽  
Author(s):  
Asish K Bhattacharya ◽  
Florian Stolz ◽  
Jürgen Kurzeck ◽  
Wolfgang Rüger ◽  
Richard R Schmidt
Keyword(s):  
Transition State ◽  
Enzyme Inhibitors ◽  
Future Generations ◽  
Arbuzov Reaction ◽  
Inhibition Kinetics ◽  
Design Synthesis ◽  
Double Stranded Dna ◽  
Structure Activity ◽  
Potential Inhibitors

The enzyme β (1[Formula: see text]4)-glucosyltransferase (BGT) catalyses the transfer of glucose from uridine diphosphoglucose (UDP-Glc) to 5-hydroxymethylcytosine (5-HMC) bases in double-stranded DNA. Potential inhibitors of BGT were developed by structure-based design and synthesized. The designed inhibitors 1–6 provide conformational mimicry of the transition state in glucosyltransfer reactions. The key synthetic steps involve a Michaelis–Arbuzov reaction followed by coupling with uridine-5'-morpholidophosphate as activated UMP derivative. The compounds were tested for in vitro inhibitory activity against BGT and the inhibition kinetics were examined. Three of the designed molecules were found to be potential inhibitors of BGT having IC50 values in the micromolar (µM) range. Useful structure–activity relationships were established which provide guidelines for the design of future generations of inhibitors of BGT.Key words: β-glucosyltransferase, transition state, enzyme inhibitors, structure-based design, synthesis.

scholarly journals Analysis of Ribonucleotide 5′-Triphosphate Analogs as Potential Inhibitors of Zika Virus RNA-Dependent RNA Polymerase by Using Nonradioactive Polymerase Assays

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Gaofei Lu ◽  
Gregory R. Bluemling ◽  
Paul Collop ◽  
Michael Hager ◽  
Damien Kuiper ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Zika Virus ◽  
Nonstructural Protein ◽  
Rna Dependent Rna Polymerase ◽  
Antiviral Compounds ◽  
Double Stranded Dna ◽  
Virus Rna ◽  
Potential Inhibitors

ABSTRACT Zika virus (ZIKV) is an emerging human pathogen that is spreading rapidly through the Americas and has been linked to the development of microcephaly and to a dramatically increased number of Guillain-Barré syndrome cases. Currently, no vaccine or therapeutic options for the prevention or treatment of ZIKV infections exist. In the study described in this report, we expressed, purified, and characterized full-length nonstructural protein 5 (NS5) and the NS5 polymerase domain (NS5pol) of ZIKV RNA-dependent RNA polymerase. Using purified NS5, we developed an in vitro nonradioactive primer extension assay employing a fluorescently labeled primer-template pair. Both purified NS5 and NS5pol can carry out in vitro RNA-dependent RNA synthesis in this assay. Our results show that Mn2+ is required for enzymatic activity, while Mg2+ is not. We found that ZIKV NS5 can utilize single-stranded DNA but not double-stranded DNA as a template or a primer to synthesize RNA. The assay was used to compare the efficiency of incorporation of analog 5′-triphosphates by the ZIKV polymerase and to calculate their discrimination versus that of natural ribonucleotide triphosphates (rNTPs). The 50% inhibitory concentrations for analog rNTPs were determined in an alternative nonradioactive coupled-enzyme assay. We determined that, in general, 2′-C-methyl- and 2′-C-ethynyl-substituted analog 5′-triphosphates were efficiently incorporated by the ZIKV polymerase and were also efficient chain terminators. Derivatives of these molecules may serve as potential antiviral compounds to be developed to combat ZIKV infection. This report provides the first characterization of ZIKV polymerase and demonstrates the utility of in vitro polymerase assays in the identification of potential ZIKV inhibitors.

Synthesis and antimicrobial activity of aryldiazenyl/arylhydrazono pyrazoles

2021 ◽  
Vol 45 (11-12) ◽  
pp. 1093-1099
Author(s):  
Abdulrhman Alsayari ◽  
Yahya I Asiri ◽  
Abdullatif Bin Muhsinah ◽  
Mohd. Zaheen Hassan
Keyword(s):  
Active Site ◽  
Phenyl Ring ◽  
Antimicrobial Agents ◽  
Inhibitory Concentration ◽  
Docking Studies ◽  
Considerable Effect ◽  
Design Synthesis ◽  
Structure Activity ◽  
Antimicrobial Evaluation

We report the design, synthesis, and in vitro antimicrobial evaluation of functionalized pyrazoles containing a hydrazono/diazenyl moiety. Among these newly synthesized derivatives, 4-[2-(4-chlorophenyl)hydrazono]-5-methyl-2-[2-(naphthalen-2-yloxy)acetyl]-2,4-dihydro-3 H-pyrazol-3-one is a promising antimicrobial agent against Staphylococcus aureus (minimum inhibitory concentration 0.19 μg mL−1). Structure–activity relationship studies reveal that the electronic environment on the distal phenyl ring has a considerable effect on the antimicrobial potential of the hybrid analogues. Molecular docking studies into the active site of S. aureus dihydrofolate reductase also prove the usefulness of hybridizing a pyrazole moiety with azo and hydrazo groups in the design of new antimicrobial agents.

Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents

2020 ◽  
Vol 44 (6) ◽  
pp. 2247-2255
Author(s):  
Qifan Zhou ◽  
Lina Jia ◽  
Fangyu Du ◽  
Xiaoyu Dong ◽  
Wanyu Sun ◽  
...  
Keyword(s):  
Biological Activity ◽  
Anticancer Agents ◽  
Biological Activities ◽  
Activity Assay ◽  
Design Synthesis ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Enhancer Of Zeste

A novel series of pyrrole-3-carboxamides targeting EZH2 have been designed and synthesized. The structure–activity relationships were summarized by combining with in vitro biological activity assay and docking results.

scholarly journals Design, Synthesis and Antibacterial Evaluation of 3-Substituted Ocotillol-Type Derivatives

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3320 ◽  
Author(s):  
Kai-Yi Wang ◽  
Zhi-Wen Zhou ◽  
Heng-Yuan Zhang ◽  
Yu-Cheng Cao ◽  
Jin-Yi Xu ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Triterpenoid Saponin ◽  
Bacterial Strains ◽  
Design Synthesis ◽  
Design And Synthesis ◽  
Good Antibacterial Activity ◽  
Structure Activity ◽  
In Vitro Antibacterial Activity ◽  
Free Hydroxyl

Antibiotic resistance has become a serious global problem that threatens public health. In our previous work, we found that ocotillol-type triterpenoid saponin showed good antibacterial activity. Based on preliminary structure-activity relationship, novel serious C-3 substituted ocotillol-type derivatives 7–26 were designed and synthesized. The in vitro antibacterial activity was tested on five bacterial strains (B. subtilis 168, S. aureus RN4220, E. coli DH5α, A. baum ATCC19606 and MRSA USA300) and compared with the tests on contrast. Among these derivatives, C-3 position free hydroxyl substituted compounds 7–14, showed good antibacterial activity against Gram-positive bacteria. Furthermore, compound 22 exhibited excellent antibacterial activity with minimum inhibitory concentrations (MIC) values of 2 μg/mL against MRSA USA300 and 4 μg/mL against B. subtilis. The structure-activity relationships of all current ocotillol-type derivatives our team synthesised were summarized. In addition, the prediction of absorption, distribution, metabolism, and excretion (ADME) properties and the study of pharmacophores were also conducted. These results can provide a guide to further design and synthesis works.

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