2. Academic Validation
  3. Hit-to-lead optimization of 2-aminoquinazolines as anti-microbial agents against Leishmania donovani

Hit-to-lead optimization of 2-aminoquinazolines as anti-microbial agents against Leishmania donovani

  • Eur J Med Chem. 2024 Apr 5:269:116256. doi: 10.1016/j.ejmech.2024.116256.
Nirmal Das 1,  Jayasree Roy 2,  Binita Patra 1,  Eleanor Saunders 3,  Dipika Sarkar 1,  Sunny Goon 1,  Bishnu Prasad Sinha 2,  Shreya Roy 2,  Swarnali Roy 1,  Jafar Sarif 2,  Purbita Bandopadhyay 2,  Subhasis Barik 2,  Suravi Mukherjee 2,  Nicole McNamara 4,  Swapna Varghese 4,  Kaylene Simpson 5,  Jonathan Baell 4,  Malcolm McConville 3,  Dipyaman Ganguly 6,  Arindam Talukdar 7
Affiliations

Affiliations

  • 1 Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, West Bengal, India.
  • 2 IICB-Translational Research Unit of Excellence, Department of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, CN6, Sector V, Salt Lake, Kolkata 700091, West Bengal, India.
  • 3 Department of Biochemistry and Pharmacology, Bio21 Institute of Molecular Science and Biotechnology (Bio21), University of Melbourne, Parkville, Victoria 3052, Australia.
  • 4 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 2052, Australia.
  • 5 Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, Victoria 3000, Australia.
  • 6 IICB-Translational Research Unit of Excellence, Department of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, CN6, Sector V, Salt Lake, Kolkata 700091, West Bengal, India. Electronic address: dipyaman@iicb.res.in.
  • 7 Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, West Bengal, India. Electronic address: atalukdar@iicb.res.in.
PMID: 38461679 DOI: 10.1016/j.ejmech.2024.116256
Abstract

Visceral leishmaniasis is a potentially fatal disease caused by Infection by the intracellular protist pathogens Leishmania donovani or Leishmania infantum. Present therapies are ineffective because of high costs, variable efficacy against different species, the requirement for hospitalization, toxicity and drug resistance. Detailed analysis of previously published hit molecules suggested a crucial role of 'guanidine' linkage for their efficacy against L. donovani. Here we report the design of 2-aminoquinazoline heterocycle as a basic pharmacophore-bearing guanidine linkage. The introduction of various groups and functionality at different positions of the quinazoline scaffold results in enhanced antiparasitic potency with modest host cell cytotoxicity using a physiologically relevant THP-1 transformed macrophage Infection model. In terms of the ADME profile, the C7 position of quinazoline was identified as a guiding tool for designing better molecules. The good ADME profile of the compounds suggests that they merit further consideration as lead compounds for treating visceral leishmaniasis.

Keywords

Guanidine linkage; Hit-to-lead; Leishmania donovani; Metabolic stability; Neglected tropical disease (NTD); Quinazoline; Scaffold-hopping; Visceral leishmaniasis (VL).

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