Title:1,3,4-Thiadiazolo (3,2-Α) Pyrimidine-6-Carbonitrile Scaffold as PARP1 Inhibitors
Volume: 21
Issue: 15
Author(s): Lakshmanan Kaviarasan, Elizabeth Eldhose, Praveen T. Krishnamurthy, Kalirajan Rajagopal, Manal Mohammed, Pulla Prudviraj and Gowramma Byran*
Affiliation:
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty- 643001, The Nilgiris, Tamil Nadu,India
Keywords:
PARP1, Schrodinger software, anticancer activity, MDA-MB-231 and MCF7 cell lines, DMBA induced model, in silico ADMET.
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.
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.
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.
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.
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.
