Identification of β-Amino alcohol grafted 1,4,5 trisubstituted 1,2,3-triazoles as potent antimalarial agents

  • Eur J Med Chem. 2016 Feb 15:109:187-98. doi: 10.1016/j.ejmech.2015.12.038.
Nalmala Devender  1 ,  Sarika Gunjan  2 ,  Stuti Chhabra  3 ,  Kartikey Singh  1 ,  Venkata Reddy Pasam  1 ,  Sanjeev K Shukla  4 ,  Abhisheak Sharma  5 ,  Swati Jaiswal  5 ,  Sunil Kumar Singh  6 ,  Yogesh Kumar  3 ,  Jawahar Lal  5 ,  Arun Kumar Trivedi  3 ,  Renu Tripathi  7 ,  Rama Pati Tripathi  8
Affiliations
  • 1. Medicinal and Process Chemistry Division, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India.
  • 2. Parasitology Division, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
  • 3. Biochemistry Division, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India.
  • 4. Sophisticated Analytical Instrument Facility Division, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India. Electronic address: [email protected].
  • 5. Pharmacokinetics & Metabolism Division, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India.
  • 6. Parasitology Division, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India.
  • 7. Parasitology Division, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India. Electronic address: [email protected].
  • 8. Medicinal and Process Chemistry Division, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India. Electronic address: [email protected].
PMID: 26774925 DOI: 10.1016/j.ejmech.2015.12.038
Abstract

In a quest to discover new drugs, we have synthesized a series of novel β-amino alcohol grafted 1,2,3-triazoles and screened them for their in vitro antiplasmodial and in vivo antimalarial activity. Among them, compounds 16 and 25 showed potent activity against chloroquine-sensitive (Pf3D7) strain with IC50 of 0.87 and 0.3 μM respectively, while compounds 7 and 13 exhibited better activity in vitro than the reference drug against chloroquine-resistance strain (PfK1) with IC50 of 0.5 μM each. Compound 25 showed 86.8% in vivo antimalarial efficacy with favorable pharmacokinetic parameters. Mechanistic studies divulged that potent compounds significantly boosted p53 protein levels to exhibit the antimalarial activity.

Keywords
Antimalarial; Antiplasmodial; Pharmacokinetics; p53 protein upregulation; β-aminoalcohol.