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  3. Discovery, SAR and mechanistic studies of quinazolinone-based acetamide derivatives in experimental visceral leishmaniasis

Discovery, SAR and mechanistic studies of quinazolinone-based acetamide derivatives in experimental visceral leishmaniasis

  • Eur J Med Chem. 2023 Sep 5;257:115524. doi: 10.1016/j.ejmech.2023.115524.
Alisha Ansari 1,  Anuradha Seth 2,  Mukul Dutta 2,  Tooba Qamar 3,  Sarita Katiyar 1,  Arvind K Jaiswal 4,  Ankita Rani 2,  Swetapadma Majhi 5,  Mukesh Kumar 6,  Rabi S Bhatta 7,  Rajdeep Guha 8,  Kalyan Mitra 5,  Koneni V Sashidhara 9,  Susanta Kar 10
Affiliations

Affiliations

  • 1 Medicinal and Process Chemistry Division, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India.
  • 2 Molecular Microbiology & Immunology Division, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India.
  • 3 Molecular Microbiology & Immunology Division, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
  • 4 Medicinal and Process Chemistry Division, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
  • 5 Electron Microscopy Unit, Sophisticated Analytical Instrument Facility Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India.
  • 6 Pharmacokinetics and Metabolism Division, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
  • 7 Pharmacokinetics and Metabolism Division, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India.
  • 8 Laboratory Animal Facility Division, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
  • 9 Medicinal and Process Chemistry Division, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India. Electronic address: [email protected].
  • 10 Molecular Microbiology & Immunology Division, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201002, India. Electronic address: [email protected].
PMID: 37290183 DOI: 10.1016/j.ejmech.2023.115524
Abstract

Towards identification of novel therapeutic candidates, a series of quinazolinone-based acetamide derivatives were synthesized and assessed for their anti-leishmanial efficacy. Amongst synthesized derivatives, compounds F12, F27 and F30 demonstrated remarkable activity towards intracellular L. donovani amastigotes in vitro, with IC50 values of 5.76 ± 0.84 μM, 3.39 ± 0.85 μM and 8.26 ± 1.23 μM against promastigotes, and 6.02 μM ± 0.52, 3.55 ± 0.22 μM and 6.23 ± 0.13 μM against amastigotes, respectively. Oral administration of compounds F12 and F27 entailed >85% reduction in organ Parasite burden in L. donovani-infected BALB/c mice and hamsters, by promoting host-protective Th1 cytokine response. In host J774 macrophages, mechanistic studies revealed inhibition of PI3K/Akt/CREB axis, resulting in a decrease of IL-10 versus IL-12 release upon F27 treatment. In silico docking studies conducted with lead compound, F27 demonstrated plausible inhibition of Leishmania prolyl-tRNA synthetase, which was validated via detection of decreased proline levels in parasites and induction of amino acid starvation, leading to G1 cell cycle arrest and autophagy-mediated programmed cell death of L. donovani promastigotes. Structure-activity analysis and study of pharmacokinetic and physicochemical parameters suggest oral availability and underscore F27 as a promising lead for anti-leishmanial drug development.

Keywords

Acetamide; Apoptosis; Autophagy; Cytokine response; Quinazolinone; Visceral leishmaniasis (VL).

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