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

Abstract

Effective chemotherapy is essential for controlling malaria. However, resistance of <i>Plasmodium falciparum</i> 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-<i>d</i>]pyrimidin-4-yl)piperazin-1-yl)methyl)-6-substitutedphenol derivatives were prepared using Petasis reaction with a view to evaluate their activities against <i>P. falciparum</i>. The development of synthesized compounds (<b>F1-F16</b>) was justified through the study of H¹ NMR, C¹³ NMR, mass spectra. Compound <b>F1</b> and <b>F2</b> were also structurally validated by single crystal X-ray diffraction analysis. All the compounds were evaluated for their <i>in vitro</i> antiplasmodial assessment against the W2 strain (chloroquine-resistant) of <i>P. falciparum</i> IC₅₀ values ranging from 0.74-6.4 μM. Two compounds, <b>F4</b> and <b>F16</b> exhibited significant activity against W2 strain of <i>P. falciparum</i> with 0.75 and 0.74 μM. The compounds (<b>F3-F6</b> and <b>F16</b>) were also evaluated for <i>in vitro</i> cytotoxicity against two cancer cell lines, human lung (A549) and cervical (HeLa) cells, which demonstrated non-cytotoxicity with significant selectivity indices. In addition, <i>in silico</i> 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-<i>d</i>]pyrimidine scaffolds may serve as models for the development of antimalarial agents.