Structure-based design and synthesis of tetrahydro-1,3,5-triazin-2-amine derivatives for anti-malarial drugs

Abstract

ABSTRACT Malaria is a life-threatening disease, caused by the protozoan parasites of the Plasmodium genus, with 241 million cases recorded globally in 2021, and 619 00 deaths in that year. In 2018, the parasite Plasmodium falciparum accounted for 99.7% of estimated malaria cases in the WHO African Region, which carried a 94% load of all malaria cases worldwide. The emergence of drug resistant strains of the parasite, and the side effects of currently used drugs indicate the urgent need for the discovery of target specific anti-malaria drugs. Anti-P. falciparum activity targeting DHFR, the K1, W2, and D6 strains has been investigated using 1,3,5-triazine derivatives. It has also been demonstrated that 1,3,5-triazine-2-amine derivatives inhibit Mycobacterium tuberculosis DHFR. Triazines have been promising therapeutic options for treating resistant malaria and TB strains. The project aimed to design and synthesize 1,3,5-triazine-2-amine derivatives for use as inhibitors of P. falciparum heat shock protein 70-1 (PfHsp70-1). In this work, a highly diverse curated seed library of ninety-nine 1,3,5 triazine-2-amine derivatives was converted from fragments to lead like compounds using structure-based methods for de novo design and fragment-based methods. These compounds were designed within the ATP active site of PfHsp70-1 by ensuring synthetic accessibility using click chemistry and robust reactions for seed growth and recombination through mutations and crossovers respectively. The diversity of these newly designed compounds was evaluated through 3D chemical space mapping of the physicochemical properties. A library of 50 unique 1,3,5 triazine-2-amine derivatives was generated, all the compounds possess drug-like properties as defined by the Lipinski rule of 5. Two compounds with a VINA binding affinity above -10 kcal/mol were synthesized. The first compound synthesized was a carbamate through isocyanate-hydroxyl coupling with N-methylimidazole, the second compound synthesized was an amide through acid-amine coupling with N,N′-dicyclohexylcarbodiimide and 1-Hydroxybenzotriazole. The third compound synthesized was an ester derived from the recombination of the alcohol from the first compound with the acid from the second compound in a sulfuric acid coupled esterification. The three compounds namely BN_01, BN_02 and BN_03 were isolated as fine needle like clear crystals with yields of 77%, 94.8% and 96%, with melting points of 280 oC, 220 oC and 249 oC respectively. This study established a functional 3D model of PfHsp70-1 as well as a library of 50 synthetically accessible lead-like anti-malarial drugs, three of which were synthesized.