Identification and structure-activity relationship (SAR) studies of carvacrol derivatives as potential anti-malarial against Plasmodium falciparum falcipain-2 protease

Amad Uddin; Vigyasa Singh; Iram Irfan; Taj Mohammad; Rahul Singh Hada; Md Imtaiyaz Hassan; Mohammad Abid; Shailja Singh

doi:10.1016/j.bioorg.2020.104142

Identification and structure-activity relationship (SAR) studies of carvacrol derivatives as potential anti-malarial against Plasmodium falciparum falcipain-2 protease

Bioorg Chem. 2020 Oct:103:104142. doi: 10.1016/j.bioorg.2020.104142. Epub 2020 Jul 28.

Authors

Amad Uddin¹, Vigyasa Singh², Iram Irfan³, Taj Mohammad⁴, Rahul Singh Hada⁵, Md Imtaiyaz Hassan⁴, Mohammad Abid⁶, Shailja Singh⁷

Affiliations

¹ Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
² Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
³ Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
⁴ Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
⁵ Department of Life Sciences, Shiv Nadar University, Gautam Buddha Nagar, Uttar Pradesh 201314, India.
⁶ Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India. Electronic address: mabid@jmi.ac.in.
⁷ Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India. Electronic address: shailja.jnu@gmail.com.

PMID: 32763521
DOI: 10.1016/j.bioorg.2020.104142

Abstract

In an effort to develop a potent anti-malarial agent against Plasmodium falciparum, a structure-guided virtual screening using an in-house library comprising 652 compounds was performed. By docking studies, we identified two compounds (JMI-105 and JMI-346) which formed significant non-covalent interactions and fit well in the binding pocket of PfFP-2. We affirmed this observation by MD simulation studies. As evident by the biochemical analysis, such as enzyme inhibition assay, Surface Plasmon Resonance (SPR), live-cell imaging and hemozoin inhibition, JMI-105 and JMI-346 at 25 µM concentration showed an inhibitory effect on purified PfFP-2. JMI-105 and JMI-346 inhibited the growth of CQ^S (3D7; IC₅₀ = 8.8 and 13 µM) and CQ^R (RKL-9; IC₅₀ = 14.3 and 33 µM) strains of P. falciparum. Treatment with compounds resulted in defect in parasite growth and development. No significant hemolysis or cytotoxicity towards human cells was observed suggesting that these molecules are non-toxic. We pursued, structural optimization on JMI-105 and in the process, SAR oriented derivatives (5a-5l) were synthesized and evaluated for growth inhibition potential. JMI-105 significantly decreased parasitemia and prolonged host survival in a murine model with P. berghei ANKA infection. The compounds (JMI-105 and JMI-346) against PfFP-2 have the potential to be used as an anti-malarial agent.

Keywords: Falcipain-2; Malaria; Plasmodium falciparum; SAR studies; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis
Antimalarials / chemistry
Antimalarials / pharmacology*
Cymenes / chemical synthesis
Cymenes / chemistry
Cymenes / pharmacology*
Cysteine Endopeptidases / metabolism*
Cysteine Proteinase Inhibitors / chemical synthesis
Cysteine Proteinase Inhibitors / chemistry
Cysteine Proteinase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Models, Molecular
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Plasmodium falciparum / enzymology
Protozoan Proteins / antagonists & inhibitors*
Protozoan Proteins / metabolism
Structure-Activity Relationship

Substances

Antimalarials
Cymenes
Cysteine Proteinase Inhibitors
Protozoan Proteins
carvacrol
Cysteine Endopeptidases
falcipain 2