Design, synthesis, and functional evaluation of triazine-based bivalent agents that simultaneously target the active site and hot spot of phosphatase Cdc25B

2021 ◽  
pp. 128265
Author(s):  
Yosei Nagaoka ◽  
Prakash Parvatkar ◽  
Go Hirai ◽  
Junko Ohkanda
Keyword(s):  
Active Site ◽  
Hot Spot ◽  
Functional Evaluation ◽  
Design Synthesis

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.

scholarly journals Design, Synthesis, and Antifungal Activity of New α-Aminophosphonates

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Zahra Rezaei ◽  
Soghra Khabnadideh ◽  
Kamiar Zomorodian ◽  
Keyvan Pakshir ◽  
Setareh Nadali ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Active Site ◽  
Catalytic Effect ◽  
Docking Study ◽  
Microsporum Canis ◽  
Pharmacological Activities ◽  
Design Synthesis ◽  
Chemical Structures ◽  
New Compounds ◽  
Time Of Reaction

α-Aminophosphonates are bioisosteres of amino acids and have several pharmacological activities. These compounds have been synthesized by various routes from reaction between amine, aldehyde, and phosphite compounds. In order to synthesize α-aminophosphonates, catalytic effect of CuCl2 was compared with FeCl3. Also all designed structures as well as griseofulvin were docked into the active site of microtubule (1JFF), using Autodock program. The results showed that the reactions were carried out in the presence of CuCl2 in lower yields, and also the time of reaction was longer in comparison with FeCl3. The chemical structures of the new compounds were confirmed by spectral analyses. The compounds were investigated for antifungal activity against several fungi in comparison with griseofulvin. An indole-derived bis(α-aminophosphonates) with the best negative ΔG in docking study showed maximum antifungal activity against Microsporum canis, and other investigated compounds did not have a good antifungal activity.

Synthesis and 4D-QSAR Studies of Alanine Hydroxamic Acid Derivatives as Aminopeptidase N Inhibitors

2019 ◽  
Vol 16 ◽  
Author(s):  
Min Gao ◽  
Qiao Li Lv ◽  
Hou Pan Zhang ◽  
Guo Gang Tu
Keyword(s):  
Biological Activity ◽  
Active Site ◽  
Hydroxamic Acid ◽  
Binding Mode ◽  
Qsar Model ◽  
Aminopeptidase N ◽  
Design Synthesis ◽  
Qsar Studies ◽  
Hydroxamic Acid Derivatives

Background: As a target for anticancer treatment, aminopeptidase N (APN) shows its overexpression on diverse malignant tumor cells and associates with cancer invasion, angiogenesis and metastasis. Objective: Design, synthesis and biological activity evaluation of alanine hydroxamic acid derivatives as APN inhibitors, and investigation the binding mode of inhibitors in the APN active site. Methods: Alanine hydroxamic acid derivatives were synthesized and evaluated for their in vitro anti-cancer activity using CCK-8 assay. Molecular docking and 4D-QSAR studies were carried out to suggest the mechanism of biological activity. Results: Compared with Bestatin, compound 9b showed the best APN inhibition activity. The putative binding mode of 9b in the APN active site was also discussed. Moreover, the robust and reliable 4D-QSAR model exhibited the following statistics: R2 = 0.9352, q2LOO = 0.8484, q2LNO =0.7920, R2Pred = 0.8739. Conclusion: Newly synthesized compounds exerted acceptable anticancer activity and further investigation on current scaffold would be beneficial.

Design, Synthesis, and Proposed Active Site Binding Analysis of Monocyclic 2-Azetidinone Inhibitors of Prostate Specific Antigen

2001 ◽  
Vol 44 (10) ◽  
pp. 1491-1508 ◽  
Author(s):  
Robert M. Adlington ◽  
Jack E. Baldwin ◽  
Gerald W. Becker ◽  
Beining Chen ◽  
Leifeng Cheng ◽  
...  
Keyword(s):  
Prostate Specific Antigen ◽  
Active Site ◽  
Specific Antigen ◽  
Design Synthesis ◽  
Binding Analysis ◽  
Site Binding

scholarly journals Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening

2019 ◽  
Vol 47 (19) ◽  
pp. 10134-10150 ◽  
Author(s):  
George T Lountos ◽  
Xue Zhi Zhao ◽  
Evgeny Kiselev ◽  
Joseph E Tropea ◽  
Danielle Needle ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Small Molecule ◽  
Anticancer Agents ◽  
Active Site ◽  
Catalytic Domain ◽  
Hot Spot ◽  
Alkylating Agents ◽  
Fragment Screening ◽  
Rational Development ◽  
Biochemical Assays

Abstract Tyrosyl DNA-phosphodiesterase I (TDP1) repairs type IB topoisomerase (TOP1) cleavage complexes generated by TOP1 inhibitors commonly used as anticancer agents. TDP1 also removes DNA 3′ end blocking lesions generated by chain-terminating nucleosides and alkylating agents, and base oxidation both in the nuclear and mitochondrial genomes. Combination therapy with TDP1 inhibitors is proposed to synergize with topoisomerase targeting drugs to enhance selectivity against cancer cells exhibiting deficiencies in parallel DNA repair pathways. A crystallographic fragment screening campaign against the catalytic domain of TDP1 was conducted to identify new lead compounds. Crystal structures revealed two fragments that bind to the TDP1 active site and exhibit inhibitory activity against TDP1. These fragments occupy a similar position in the TDP1 active site as seen in prior crystal structures of TDP1 with bound vanadate, a transition state mimic. Using structural insights into fragment binding, several fragment derivatives have been prepared and evaluated in biochemical assays. These results demonstrate that fragment-based methods can be a highly feasible approach toward the discovery of small-molecule chemical scaffolds to target TDP1, and for the first time, we provide co-crystal structures of small molecule inhibitors bound to TDP1, which could serve for the rational development of medicinal TDP1 inhibitors.

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