2. Academic Validation
  3. Blood-stage antimalarial activity, favourable metabolic stability and in vivo toxicity of novel piperazine linked 7-chloroquinoline-triazole conjugates

Blood-stage antimalarial activity, favourable metabolic stability and in vivo toxicity of novel piperazine linked 7-chloroquinoline-triazole conjugates

  • Eur J Med Chem. 2023 Nov 25:264:115969. doi: 10.1016/j.ejmech.2023.115969.
Amad Uddin 1,  Sonal Gupta 2,  Rumaisha Shoaib 1,  Babita Aneja 3,  Iram Irfan 3,  Kanika Gupta 2,  Neha Rawat 2,  Jill Combrinck 4,  Bhumika Kumar 5,  Mohd Aleem 6,  Phool Hasan 3,  Mukesh C Joshi 7,  Yashpal S Chhonker 8,  Muhammad Zahid 9,  Afzal Hussain 10,  Kailash Pandey 11,  Mohamed F Alajmi 10,  Daryl J Murry 8,  Timothy J Egan 4,  Shailja Singh 12,  Mohammad Abid 13
Affiliations

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 Department of Chemistry, University of Cape Town, Private Bag, Rondebosch, Cape Town, 7701, South Africa.
  • 5 Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India; National Institute of Malaria Research, New Delhi, 110077, India.
  • 6 Division of Behavioral Neuroscience, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, India.
  • 7 Department of Chemistry, Kirori Mal College, University of Delhi, Delhi, 110007, India.
  • 8 Department of Pharmacy Practice and Science College of Pharmacy, University of Nebraska Medical Center, 986145, Nebraska Medical Center, Omaha, NE, 68198-6145, USA.
  • 9 Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, 986145, Nebraska Medical Center, Omaha, NE, 68198-6145, USA.
  • 10 Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
  • 11 National Institute of Malaria Research, New Delhi, 110077, India.
  • 12 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India. Electronic address: shailja.jnu@gmail.com.
  • 13 Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India. Electronic address: mabid@jmi.ac.in.
PMID: 38039787 DOI: 10.1016/j.ejmech.2023.115969
Abstract

The persistence of drug resistance poses a significant obstacle to the advancement of efficacious malaria treatments. The remarkable efficacy displayed by 1,2,3-triazole-based compounds against Plasmodium falciparum highlights the potential of triazole conjugates, with diverse pharmacologically active structures, as potential antimalarial agents. We aimed to synthesize 7-dichloroquinoline-triazole conjugates and their structure-activity relationship (SAR) derivatives to investigate their anti-plasmodial activity. Among them, QP11, featuring a m-NO2 substitution, demonstrated efficacy against both chloroquine-sensitive and -resistant Parasite strains. QP11 selectively inhibited FP2, a cysteine Protease involved in hemoglobin degradation, and showed synergistic effects when combined with chloroquine. Additionally, QP11 hindered hemoglobin degradation and hemozoin formation within the Parasite. Metabolic stability studies indicated high stability of QP11, making it a promising antimalarial candidate. In vivo evaluation using a murine malaria model demonstrated QP11's efficacy in eradicating Parasite growth without neurotoxicity, presenting it as a promising compound for novel antimalarial development.

Keywords

Antimalarials; Blood-stage; Falcipain; Hemozoin inhibition; In vivo; Metabolic stability.

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