Molecular docking and antimalarial evaluation of hybrid para-aminobenzoic acid 1,3,5 triazine derivatives via inhibition of Pf-DHFR

Abstract

In this study, a structurally guided pharmacophore hybridization strategy is used to combine the two key structural scaffolds, para-aminobenzoic acid (PABA), and 1,3,5 triazine in search of new series of antimalarial agents. A combinatorial library of 100 compounds was prepared in five different series as [4A (1–22), 4B (1–21), 4 C (1–20), 4D (1–19) and 4E (1–18)] using different primary and secondary amines, from where 10 compounds were finally screened out through molecular property filter analysis and molecular docking study as promising PABA substituted 1,3,5-triazine scaffold as an antimalarial agent. The docking results showed that compounds 4A12 and 4A20 exhibited good binding interaction with Phe58, IIe164, Ser111, Arg122, Asp54 (−424.19 to −360.34 kcal/mol) and Arg122, Phe116, Ser111, Phe58 (−506.29 to −431.75 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR. These compounds were synthesized by conventional as well as microwave-assisted synthesis and characterized by different spectroscopic methods. In-vitro antimalarial activity results indicated that two compounds 4A12 and 4A20 showed promising antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of Plasmodium falciparum with IC₅₀ (1.24–4.77 μg mL⁻¹) and (2.11–3.60 μg mL⁻¹). These hybrid PABA substituted 1,3,5-triazine derivatives might be used in the lead discovery towards a new class of Pf-DHFR inhibitors.

Communicated by Ramaswamy H. Sarma

Keywords:

• PABA
• 1
• 3
• 5-triazine
• docking
• microwave synthesis
• antimalarial

Acknowledgments

The authors would like to extend their sincere appreciation to the SAIF, Punjab University for providing the spectral scans of the synthesized compounds.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The author(s) reported that the present study was funded by Department of Science and Technology (DST), New Delhi, India, via Grant/Award Number EMR/2017/00708.