New pyrazolylpyrazoline derivatives as dual acting antimalarial-antileishamanial agents: synthesis, biological evaluation and molecular modelling simulations

Abstract

Promising inhibitory activities of the parasite multiplication were obtained upon evaluation of in vivo antimalarial activities of new pyrazolylpyrazoline derivatives against Plasmodium berghei infected mice. Further evaluation of 5b and 6a against chloroquine-resistant strain (RKL9) of P. falciparum showed higher potency than chloroquine. In vitro antileishmanial activity testing against Leishmania aethiopica promastigote and amastigote forms indicated that 5b, 6a and 7b possessed promising activity compared to miltefosine and amphotericin B deoxycholate. Moreover, antileishmanial activity reversal of the active compounds via folic and folinic acids showed comparable results to the positive control trimethoprim, indicating an antifolate mechanism via targeting leishmanial DHFR and PTR1. The compounds were non-toxic at 125, 250 and 500 mg/kg. In addition, docking of the most active compound against putative malarial target Pf-DHFR-TS and leishmanial PTR1 rationalised the observed activities. Molecular dynamics simulations confirmed a stable and high potential binding of 7a against leishmanial PTR1.

Keywords:

• Pyrazoline derivatives
• antimalarial evaluation
• antileishmanial evaluation
• antifolate mechanism
• molecular docking
• molecular dynamics

Acknowledgement

TMI would like to acknowledge Bibliotheca Alexandrina High-Performance Computing (BA-HPC) for granting access to perform the molecular dynamics simulations. The authors would like to thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code: (22UQU4290565DSR64).

Author contributions

All authors have given approval to the final version of the manuscript. All authors agree to be accountable for the content of the work.

Ethics statements

The animal study was reviewed and approved by the protocols used in this study followed the guidelines set in ‘The Guide for the Care and Use of Laboratory Animals’, and obtained approval by Animal Care & Use Committee (ACUC), Faculty of Pharmacy, Alexandria University, No. ACUC17/18 at 29/4/2017.

Disclosure statement

The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.