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  3. Design, synthesis, and biological evaluation of quinoline-piperazine/pyrrolidine derivatives as possible antileishmanial agents

Design, synthesis, and biological evaluation of quinoline-piperazine/pyrrolidine derivatives as possible antileishmanial agents

  • Eur J Med Chem. 2023 Oct 7:261:115863. doi: 10.1016/j.ejmech.2023.115863.
Sarita Katiyar 1,  Karthik Ramalingam 2,  Abhishek Kumar 3,  Alisha Ansari 1,  Amol Chhatrapati Bisen 4,  Garvita Mishra 5,  Sachin Nashik Sanap 4,  Rabi Sankar Bhatta 6,  Bidyut Purkait 7,  Neena Goyal 8,  Koneni V Sashidhara 9
Affiliations

Affiliations

  • 1 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India.
  • 2 Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
  • 3 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
  • 4 Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India.
  • 5 Molecular Microbiology & Immunology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
  • 6 Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
  • 7 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India; Molecular Microbiology & Immunology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
  • 8 Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India. Electronic address: neena_goyal@cdri.res.in.
  • 9 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Sophisticated Analytical Instrument Facility & Research, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, U.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India. Electronic address: kv_sashidhara@cdri.res.in.
PMID: 37837672 DOI: 10.1016/j.ejmech.2023.115863
Abstract

In pursuance of our efforts to expand the scope of novel antileishmanial entities, a series of thirty-five quinoline-piperazine/pyrrolidine, and other heterocyclic amine derivatives were synthesized via a molecular hybridization approach and examined against intracellular amastigotes of luciferase-expressing Leishmania donovani. The preliminary in vitro screening suggests that twelve compounds in the series exhibited better inhibition against amastigote form with good IC50 values ranging from 2.09 to 8.89 μM and lesser cytotoxicity in contrast to the standard drug miltefosine (IC50 9.25 ± 0.17 μM). Based on the satisfactory selectivity index (SI), two compounds were tested for in vivo leishmanicidal efficacy against Leishmania donovani/golden hamster model. Compounds 33 and 46 have shown significant inhibition of 56.32%, and 49.29%, respectively, in vivo screening at a daily dose of 50 mg/kg for 5 days. The pharmacokinetic results confirmed that 33 and 46 have satisfactory IP exposure with adequate parameters. Collectively, Compound 33 was identified as the most significant potential lead that could be employed as a prototype for future optimizations.

Keywords

Antileishmanial activity; Leishmania donovani; Quinoline-piperazine/pyrrolidine.

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