Novel Glu-based pyrazolo[3,4-d]pyrimidine analogues: design, synthesis and biological evaluation as DHFR and TS dual inhibitors

Mater Mahnashi; Mohammed Merae Alshahrani; Amer Al Ali; Abdulaziz Asiri; Mahrous A Abou-Salim

doi:10.1080/14756366.2023.2203879

Novel Glu-based pyrazolo[3,4-d]pyrimidine analogues: design, synthesis and biological evaluation as DHFR and TS dual inhibitors

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2203879. doi: 10.1080/14756366.2023.2203879.

Authors

Mater Mahnashi¹, Mohammed Merae Alshahrani², Amer Al Ali³, Abdulaziz Asiri³, Mahrous A Abou-Salim⁴

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, Najran University, Najran, Saudi Arabia.
² Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, Najran, Saudi Arabia.
³ Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, University of Bisha, Bisha, Saudi Arabia.
⁴ Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt.

Abstract

A novel series of multifunctional pyrazolo[3,4-d]pyrimidine-based glutamate analogs (6a-l and 7a,b) have been designed and synthesized as antifolate anticancer agents. Among the tested compounds, 6i exhibited the most potent anti-proliferative activity towards NSCLC, CNS, Ovarian, Prostate, Colon, Melanoma, Breast, and Renal cancers with good to weak cytostatic activity and non-lethal actions. 6i demonstrated higher selectivity for cancer than normal cells. 6i could significantly increase the accumulation of S-phase cells during the cell cycle distribution of cancer cells with high potency in the induction of apoptosis. The results unveiled that 6i probably acts through dual inhibition of DHFR and TS enzymes (IC₅₀ = 2.41 and 8.88 µM, correspondingly). Docking studies of 6i displayed that N1-p-bromophenyl and C3-Methyl groups participate in substantial hydrophobic interactions. The drug-likeness features inferred that 6i met the acceptance criteria of Pfizer. Taking together, 6i could be a promising prototype for further optimization as an effective anticancer drug.

Keywords: DHFR; Glu; NCI; TS; pyrazolo[34-d]pyrimidine.

MeSH terms

Antineoplastic Agents* / chemistry
Cell Proliferation
Drug Design
Drug Screening Assays, Antitumor
Folic Acid Antagonists*
Humans
Molecular Structure
Neoplasms*
Pyrimidines / chemistry
Structure-Activity Relationship

Substances

Pyrimidines
Antineoplastic Agents
Folic Acid Antagonists

Grants and funding

This research was funded by Deanship of Scientific Research at Najran University, grant number NU/DRP/MRC/12/1”.