Identification of new oxospiro chromane quinoline-carboxylate antimalarials that arrest parasite growth at ring stage

Abstract

Malaria still threatens half the globe population despite successful Artemisinin-based combination therapy. One of the reasons for our inability to eradicate malaria is the emergence of resistance to current antimalarials. Thus, there is a need to develop new antimalarials targeting Plasmodium proteins. The present study reported the design and synthesis of 4, 6 and 7-substituted quinoline-3-carboxylates 9(a–o) and carboxylic acids 10(a–b) for the inhibition of Plasmodium N-Myristoyltransferases (NMTs) using computational biology tools followed by chemical synthesis and functional analysis. The designed compounds exhibited a glide score of −9.241 to −6.960 kcal/mol for PvNMT and −7.538 kcal/mol for PfNMT model proteins. Development of the synthesized compounds was established via NMR, HRMS and single crystal X-ray diffraction study. The synthesized compounds were evaluated for their in vitro antimalarial efficacy against CQ-sensitive Pf3D7 and CQ-resistant PfINDO lines followed by cell toxicity evaluation. In silico results highlighted the compound ethyl 6-methyl-4-(naphthalen-2-yloxy)quinoline-3-carboxylate (9a) as a promising inhibitor with a glide score of −9.084 kcal/mol for PvNMT and −6.975 kcal/mol for PfNMT with IC₅₀ values of 6.58 µM for Pf3D7 line. Furthermore, compounds 9n and 9o exhibited excellent anti-plasmodial activity (Pf3D7 IC₅₀ = 3.96, 6.71 µM, and PfINDO IC₅₀ = 6.38, 2.8 µM, respectively). The conformational stability of 9a with the active site of the target protein was analyzed through MD simulation and was found concordance with in vitro results. Thus, our study provides scaffolds for the development of potent antimalarials targeting both Plasmodium vivax and Plasmodium falciparum.

Communicated by Ramaswamy H. Sarma

Keywords:

• Docking & MD simulation
• homology modeling
• Plasmodium N-myristoyltransferase inhibitors
• Pf3D7 and PfINDO
• X-ray crystallography

Acknowledgments

The authors EJ and HM wish to acknowledge the Indian Council of Medical Research (Government of India), New Delhi, India for providing financial support during the study as Research Associate (File No. BIC/11 (39) 2015) and Senior Research Fellowship (Award No. 45/02/2020-Nan/BMS), respectively. Authors also like to acknowledge Dr. Imran A. Khan, Department of Chemistry, Jamia Hamdard, New Delhi for his continuous discussion and suggestions during the study. PM acknowledges the Science and Engineering Research Board (SERB), Department of Science & Technology, Government of India for the J. C. Bose Fellowship (Grant No. JCB/2020/000015) for providing financial support during the study. The authors acknowledge SCFBio, Indian Institute of Technology, Delhi for providing supercomputing facilities to conduct the study.

Author contributions

Ehtesham Jameel: In silico studies, chemical synthesis, characterizations and evaluation of results, visualization, writing- original draft preparation and revision of MS. Hari Madhav: In silico studies, chemical synthesis, characterizations and evaluation of results, visualization, writing- original draft preparation and revision of the MS. Prakhar Agrawal: Antimalarial screening and evaluation of the results. Md Kausar Raza: Characterization, crystal study and evaluation of the results. Saiema Ahmadi and Nikhat Manzoor: Hemolysis assay and evaluation of the results, writing. Nida Shahid, Kashfa Shaheen and Jitendra Kumar: Chemical synthesis. Abdur Rahman: Synthesis of intermediate 8. Chhaya Haresh Gajra and Dinesh Gupta: Homology modeling and revision of the MS. Ashma Khan and Shahid M. Nayeem: Molecular dynamics simulation, analysis of the results, writing. Md. Zubbair Malik and Md Ali Imam: Computational study. Md Kalamuddin and Asif Mohammad: Antimalarial screening. Pawan Malhotra: Design and supervision of antimalarial screening, evaluation of the results, reviewing and editing original draft and revision of the MS. Nasimul Hoda: Conceptualization, methodology, resources, supervision, investigation, reviewing and editing the original draft, arrangement of funds and revision of the MS.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.