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

• Published in: MedChemComm 2021-06, Vol.12 (6), p.97-981
• Main Authors: Pal, Kavita, Raza, Md Kausar, Legac, Jenny, Ataur Rahman, Md, Manzoor, Shoaib, Rosenthal, Philip J, Hoda, Nasimul
• Format: Article
• Language: English
• Subjects: Antimalarial agents; Antiprotozoal agents; Cervix; Chemistry; Chemotherapy; Chloroquine; Crystal structure; Crystallography; Cytotoxicity; Erythrocytes; Evaluation; Lung cancer; Malaria; Mass spectra; NMR; Nuclear magnetic resonance; Physiochemistry; Plasmodium falciparum; Selectivity; Single crystals; Toxicity; Tumor cell lines; Vector-borne diseases; X-ray diffraction
• ISSN: 2632-8682; 2040-2503; 2632-8682; 2040-2511
• DOI: 10.1039/d1md00038a

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 H 1 NMR, C 13 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 IC 50 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. This work reports the design and synthesis of a library of thieno[2,3- d ]pyrimidine derivatives and screened for their in vitro anti-plasmodial and cytotoxic assessment to identify a lead compound in the development of potential antimalarials.