Synthesis, Aromatase Inhibitory, Antiproliferative and Molecular Modeling Studies of Functionally Diverse D-Ring Pregnenolone Pyrazoles

2020 ◽  
Vol 20 ◽  
Author(s):  
Abid H. Banday ◽  
Bahjat A. Saeed ◽  
Najim A. Al-Masoudi
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Aromatase Inhibitors ◽  
Docking Study ◽  
Biological Evaluation ◽  
Type I ◽  
Binding Modes ◽  
Molecular Docking Study ◽  
Functionally Diverse ◽  
Antiproliferative Activities

Background:: Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormone- dependent breast cancer. Design of new steroidal aromatase inhibitors becomes imperative. Objective:: Synthesis and biological evaluation of two classes of structurally and functionally diverse D-ring pregnenolone pyrazoles as type I aromatase inhibitors and antiproliferative agents. Methods:: Pregnenolone (1) was converted to 3β-hydroxy-21-hydroxymethylidenepregn-5-en-20-one (2) which upon cyclization with phenylhydrazine generated regioisomeric pairs of pyrazoles 4 and 5. Further, Knoevenagel condensation of pregnenolone (1) with 3-oxo-3-phenylpropanenitrile (6) produced 2-benzoyl-3-(3-hydroxy-androstan-5-ene-20-ylidene)-but-2-enenitrile (7) which upon cyclization with hydrazine or phenylhydrazine generated the pyrazoles 8 and 9. All new steroidal derivatives were tested for their aromatase inhibition activity using dibenzylfluorescein (DBF) based florescence assay developed by Stresser et al. Antiproliferative activities were measured using Sulforhodamine B assay. The activities were promising and there was coherence between aromatase inhibitory and antiproliferative activities. Results:: The study reveals the immense potential of pregnenolone pyrazoles as aromatase inhibitors for treatment of breast cancer. Molecular docking studies prove efficient binding of the new steroidal analogs on human placental aromatase. Conclusions:: In the overall study, most of the compounds exhibited potential activity for treatment of hormone dependent breast cancer. Compounds 4c and 4d were found to be the most promising pharmacons. Furthermore, compound 4c and 4d were applied for their molecular docking study on human placental aromatase to predict their possible binding modes with the enzyme. These studies revealed that such molecules have high scope and potential for further investigation towards treatment of estrogen dependent breast cancer.

Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities

2020 ◽  
Vol 16 (7) ◽  
pp. 892-902 ◽  
Author(s):  
Aida Iraji ◽  
Mahsima Khoshneviszadeh ◽  
Pegah Bakhshizadeh ◽  
Najmeh Edraki ◽  
Mehdi Khoshneviszadeh
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Competitive Inhibition ◽  
Docking Study ◽  
Biological Evaluation ◽  
Primary Response ◽  
Ratio Method ◽  
Molecular Docking Study ◽  
Metal Chelating

Background: Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting step of the melanin formation. Natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti– tyrosinase agents. Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated. Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site. Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex. Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.

scholarly journals Interaction between DNA, Albumin and Apo-Transferrin and Iridium(III) Complexes with Phosphines Derived from Fluoroquinolones as a Potent Anticancer Drug

2021 ◽  
Vol 14 (7) ◽  
pp. 685
Author(s):  
Sandra Amanda Kozieł ◽  
Monika Katarzyna Lesiów ◽  
Daria Wojtala ◽  
Edyta Dyguda-Kazimierowicz ◽  
Dariusz Bieńko ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Serum Proteins ◽  
Docking Study ◽  
Minor Groove ◽  
Docking Studies ◽  
Minor Groove Binding ◽  
Binding Modes ◽  
Groove Binding ◽  
Molecular Docking Study ◽  
Threading Intercalation

A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) radicals generation. Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, circular dichroism, and molecular docking studies. DNA binding experiments established that the complexes interact with DNA by moderate intercalation and predominance of minor groove binding without the capability to cause a double-strand cleavage. The molecular docking study confirmed two binding modes: minor groove binding and threading intercalation with the fluoroquinolone part of the molecule involved in pi stacking interactions and the Ir(III)-containing region positioned within the major or minor groove. Fluorescence spectroscopic data (HSA and apo-Tf titration), together with molecular docking, provided evidence that Ir(III) complexes can bind to the proteins in order to be transferred. All the compounds considered herein were found to bind to the tryptophan residues of HSA within site I (subdomain II A). Furthermore, Ir(III) complexes were found to dock within the apo-Tf binding site, including nearby tyrosine residues.

scholarly journals Synthesis, Biological Evaluation and Molecular Docking Study of Hydrazone-Containing Pyridinium Salts as Cholinesterase Inhibitors

2016 ◽  
Vol 64 (9) ◽  
pp. 1281-1287 ◽  
Author(s):  
Sulunay Parlar ◽  
Gulsah Bayraktar ◽  
Ayse Hande Tarikogullari ◽  
Vildan Alptüzün ◽  
Ercin Erciyas
Keyword(s):  
Molecular Docking ◽  
Cholinesterase Inhibitors ◽  
Docking Study ◽  
Biological Evaluation ◽  
Pyridinium Salts ◽  
Molecular Docking Study

Synthesis, Biological Evaluation of ortho-Carboxamidostilbenes as Potential Inhibitors of Hyperglycemic Enzymes, and Molecular Docking Study

2021 ◽  
pp. 131007
Author(s):  
Norhadi Mohamad ◽  
Phua Yoong Hui ◽  
Mohamad Hafizi Abu Bakar ◽  
Mohammad Tasyriq Che Omar ◽  
Habibah A. Wahab ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Study ◽  
Biological Evaluation ◽  
Molecular Docking Study ◽  
Potential Inhibitors

Facile synthesis of new N-sulfonamidyl-4-thiazolidinone derivatives and their biological evaluation

2016 ◽  
Vol 40 (4) ◽  
pp. 3047-3058 ◽  
Author(s):  
Dnyaneshwar D. Subhedar ◽  
Mubarak H. Shaikh ◽  
Firoz A. Kalam Khan ◽  
Jaiprakash N. Sangshetti ◽  
Vijay M. Khedkar ◽  
...  
Keyword(s):  
Ionic Liquid ◽  
Molecular Docking ◽  
Antioxidant Properties ◽  
Docking Study ◽  
Biological Evaluation ◽  
Facile Synthesis ◽  
Molecular Docking Study ◽  
One Pot

A one-pot three-component facile synthesis of N-sulfonamidyl-4-thiazolidinone derivatives using a [HDBU][HSO4] reusable ionic liquid was carried out, together with an investigation into their antifungal and antioxidant properties and a molecular docking study.

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