Visible-light driven regioselective synthesis, characterization and binding studies of 2-aroyl-3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidines with DNA and BSA using biophysical and computational techniques

Ranjana Aggarwal,Naman Jain,Shilpa Sharma,Heerak Chugh,Ramesh Chandra,Prince Kumar,Gyan Prakash Dubey

doi:10.1038/s41598-021-01037-4

Abstract

In recent times, fused azaheterocycles emerged as impressive therapeutic agents. Binding studies of such azaheterocycles with biomolecules is an important subject for pharmaceutical and biochemical studies aiming at the design and development of new drugs. Fused heterocyclic scaffolds, such as thiazolopyrmidines have long been used in the pharmaceutical industry for the treatment of various diseases. In this study, we have accomplished a regioselective synthesis of 2-aroyl-3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidines by the reaction of tetrahydropyrimidine-2(H)-thione with α-bromo-1,3-diketones, generated in situ from 1,3-diketones and NBS, using visible light as an inexpensive, green and renewable energy source under mild reaction conditions with wide-ranging substrate scope. The regioisomer was characterized unambiguously by 2D-NMR [1H-13C] HMBC and [1H-13C] HMQC spectroscopy. In silico toxicity data analysis showed the low toxicity risks of the synthesized compounds. Computational molecular docking studies were carried out to examine the interaction of thiazolo[3,2-a]pyrimidines with calf-thymus DNA (ct-DNA) and Bovine Serum Albumin (BSA). Moreover, different spectroscopic approaches viz. steady-state fluorescence, competitive displacement assay, UV–visible and circular dichroism (CD) along with viscosity measurements were employed to investigate the binding mechanisms of thiazolo[3,2-a]pyrimidines with DNA and BSA. The results thus obtained revealed that thiazolo[3,2-a]pyrimidines offer groove bindings with DNA and showed moderate bindings with BSA.

Highlights

Aldehydes with 2-aminothiazole and malononitrile/diethyl malonate/ethyl 2-cyanoacetate in piperidine catalyzed ethanolic reflux[11,12]
Regioselective synthesis of a series of 2-aroyl/heteroaroyl-3-methyl-6,7-dihydro-5H-thiazolo[3,2-a] pyrimidines 4a–h out of the four possible regioisomers has been accomplished using unsymmetrical 1,3-diketones 1a–h and tetrahydropyrimidine-2-(H)-thione 2 as simple synthons in presence of visible light conditions and the products are obtained in excellent yields
The synthesized compounds have been characterized by IR, 1H and 13C NMR and 2D-NMR [(1H-13C) HSQC and (1H-13C) HMBC)]

Summary

Introduction

Aldehydes with 2-aminothiazole and malononitrile/diethyl malonate/ethyl 2-cyanoacetate in piperidine catalyzed ethanolic reflux[11,12]. After the reaction conditions were optimized, differently substituted aryl and heteroaryl 1,3-diketones 1a–h were employed to react with tetrahydropyrimidine-2-thione 2 to generate a series of 2-aroyl/heteroaroyl-3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidines 4a–h where all the employed diketones 1a–h displayed excellent selectivity and the products 4a–h were obtained in good yields (Fig. 2). Outcomes of this study showed that among the synthesized thiazolopyrimidine derivatives, compound with 2,4-dichlorosubstitution 4g binds with DNA dodecamer d(CGCGAATTCGCG)[2] (PDB ID:1BNA) more efficiently than other derivatives with a maximum docking score of − 7.5 kcal/mol (Table 5).

Results

Conclusion