Design, synthesis, crystal structure and anti-plasmodial evaluation of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives

Abstract

Effective chemotherapy is essential for controlling malaria. However, resistance of Plasmodium falciparum to existing antimalarial drugs has undermined attempts to control and eventually eradicate the disease. In this study, a series of 2-((substituted)(4-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)methyl)-6-substitutedphenol derivatives were prepared using Petasis reaction with a view to evaluate their activities against P. falciparum. The development of synthesized compounds (F1–F16) was justified through the study of H¹ NMR, C¹³ NMR, mass spectra. Compound F1 and F2 were also structurally validated by single crystal X-ray diffraction analysis. All the compounds were evaluated for their in vitro antiplasmodial assessment against the W2 strain (chloroquine-resistant) of P. falciparum IC₅₀ values ranging from 0.74–6.4 μM. Two compounds, F4 and F16 exhibited significant activity against W2 strain of P. falciparum with 0.75 and 0.74 μM. The compounds (F3–F6 and F16) were also evaluated for in vitro cytotoxicity against two cancer cell lines, human lung (A549) and cervical (HeLa) cells, which demonstrated non-cytotoxicity with significant selectivity indices. In addition, in silico ADME profiling and physiochemical properties predicts drug-like properties with a very low toxic effect. Thus, all these results indicate that tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine scaffolds may serve as models for the development of antimalarial agents.