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  3. Identification, in-vitro anti-plasmodial assessment and docking studies of series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide molecular hybrids as potential antimalarial agents

Identification, in-vitro anti-plasmodial assessment and docking studies of series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide molecular hybrids as potential antimalarial agents

  • Eur J Med Chem. 2023 Feb 15:248:115055. doi: 10.1016/j.ejmech.2022.115055.
Kavita Pal 1,  Md Kausar Raza 2,  Jenny Legac 3,  Abdur Rahman 4,  Shoaib Manzoor 1,  Souvik Bhattacharjee 4,  Philip J Rosenthal 3,  Nasimul Hoda 5
Affiliations

Affiliations

  • 1 Drug Design and Synthesis Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi, 110025, India.
  • 2 Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, 560012, India.
  • 3 Department of Medicine, University of California, San Francisco, CA, USA.
  • 4 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.
  • 5 Drug Design and Synthesis Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi, 110025, India. Electronic address: [email protected].
PMID: 36621136 DOI: 10.1016/j.ejmech.2022.115055
Abstract

Malaria is the most lethal parasitic infections in the world. To address the emergence of drug resistance to current antimalarials, here we report the design and synthesis of new series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide hybrids by using multicomponent Petasis reaction as the key step and evaluated in vitro for their antimalarial effectiveness. The structure of all the compounds were confirmed by NMR Spectroscopy and mass spectrometry. Most of the compounds showed potent antimalarial activity against both CQ-sensitive (3D7) and CQ-resistant (W2) strains. A8, A5, and A4 are the most potent compounds that showed excellent anti-plasmodial activity against CQ-resistant strain in the nanomolar range with IC50 values 55.7 nM, 60.8 nM, and 68.0 nM respectively. To assess the Parasite selectivity, the in vitro cytotoxicity of selected compounds (A3-A6, A8) was tested against HPL1D cells, demonstrating low cytotoxicity with high selectivity indices. Furthermore, these compounds were also evaluated on two additional human cancerous cell lines (A549 and MDA-MB-231), confirming their Anticancer effectiveness. The in vitro hemolysis assay also showed the non-toxicity of these compounds on normal uninfected human RBCs. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The in silico ADMET profiling also revealed promising physicochemical and pharmacokinetic parameters for the most active hybrids, which provide strong vision for further development of potential antimalarials.

Keywords

ADMET properties; Antimalarial activity; Docking study; Hemolysis assay; Petasis reaction; Tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide.

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