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1,3,4-Thiadiazolo (3,2-Α) Pyrimidine-6-Carbonitrile Scaffold as PARP1 Inhibitors.
- Source :
-
Anti-cancer agents in medicinal chemistry [Anticancer Agents Med Chem] 2021; Vol. 21 (15), pp. 2050-2065. - Publication Year :
- 2021
-
Abstract
- Background: 1,3,4-thiadiazolo pyrimidine is a lead molecule that is versatile for a wide variety of biological activities and in continuation of our interest in establishing some novel heterocyclic compounds for antitumor activity.<br />Objective: The objective of the study was to synthesize a series of 5-amino-7-(substituted aldehyde)-2[(naphthalene- 2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives and evaluate their possible in vitro and in vivo anticancer activity.<br />Methods: Herein, we report the synthetic scheme, which was followed for the preparation of a series of title compounds B1- B9 outlined in scheme 1. The intermediate 5-[(naphthalen-2- yloxy)methyl]-1,3,4-thiadiazolo- 2-amine was prepared by heating 2-naphthoxyacetic acid and thiosemicarbazide in the presence of phosphoryl chloride at a temperature of 65-75°C. The obtained compound reacted with malononitrile and an appropriate amount of aromatic and heteroaromatic aldehydes in refluxing ethanol yielded 5-amino-7-(substituted aldehyde)-2[(naphthalene-2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives (B1 - B9). The purity of the synthesized compounds was ensured by various spectral analyses.<br />Results: In in silico molecular docking studies, compounds B3 and B9 show binding affinity like known PARP1 inhibitor olaparib. The cellular evaluation indicates that the anticancer profile of compounds B1, B3, and B9 is significant when compared to the standard drug (olaparib) against MDA-MB-232 cell line and compounds B3, B6, and B7 are the most active against MCF-7 cell lines. The most active compound B3 was subjected to acute oral toxicity studies by OECD 423 guidelines and in vivo anti-cancer studies were carried out using DMBA induced model.<br />Conclusion: The in silico docking study of the newly synthesized compounds was performed; the results showed good binding mode in the active site of PARP1 enzyme. In silico ADME properties of synthesized compounds were also studied and showed good drug-like properties.<br /> (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Mice
Molecular Docking Simulation
Molecular Structure
Poly (ADP-Ribose) Polymerase-1 metabolism
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Pyrimidines chemical synthesis
Pyrimidines chemistry
Thiadiazoles chemical synthesis
Thiadiazoles chemistry
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Pyrimidines pharmacology
Thiadiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1875-5992
- Volume :
- 21
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Anti-cancer agents in medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33327923
- Full Text :
- https://doi.org/10.2174/1871520621666201216095018