Target Guided Synthesis of 5-Benzyl-2,4-diamonopyrimidines: Their Antimalarial Activities and Binding Affinities to Wild Type and Mutant Dihydrofolate Reductases from Plasmodium falciparum

Abstract

The resistance to pyrimethamine (PYR) of Plasmodium falciparum arising from mutation at position 108 of dihydrofolate reductase (pfDHFR) from serine to asparagine (S108N) is due to steric interaction between the bulky side chain of N108 and Cl atom of the 5-p-Cl aryl group of PYR, which consequently resulted in the reduction in binding affinity between the enzyme and inhibitor. Molecular modeling suggested that the flexible antifolate, such as trimethoprim (TMP) derivatives, could avoid this steric constraint and should be considered as new, potentially effective compounds. The hydrophobic interaction between the side chain of inhibitor and the active site of the enzyme around position 108 was enhanced by the introduction of a longer and more hydrophobic side chain on TMP's 5-benzyl moiety. The prepared compounds, especially those bearing aromatic substituents, exhibited better binding affinities to both wild type and mutant enzymes than the parent compound. Binding affinities of these compounds correlated well with their antimalarial activities against both wild type and resistant parasites. Molecular modeling of the binding of such compounds with pfDHFR also supported the experimental data and clearly showed that aromatic substituents play an important role in enhancing binding affinity. In addition, some compounds with 6-alkyl substituents showed relatively less decrease in binding constants with the mutant enzymes and relatively good antimalarial activities against the parasites bearing the mutant enzymes.

Synthesis of 2-(aminomethyl)aziridines and their microwave-assisted ring opening to 1,2,3-triaminopropanes as novel antimalarial pharmacophores

“…In recent years, the synthesis of functionalized adenines has gained much interest due to the pronounced biological activities, such as antitumor and antiviral, associated to this class of compounds [46,47,48]. Besides purines, also pyrimidines are known to be of importance as lead compounds in medicinal chemistry [48,49,50]. In that respect, thymine was used as a nucleophile toward the preparation of 2-[(2,4-dioxo-5-methylpyrimidin-1-yl)methyl]aziridines 2d,e upon treatment of 2-(bromomethyl)aziridines 1 with one equiv of thymine and one equiv of NaH in DMF at 80 °C for 3 hours (Table 1, entries 4-5).…”

“…falciparum (IC 50 -values between 48.3 and 18.0 M), and low (2i-k) or no (2h) cytotoxicity (Table 2).…”

A common feature-based 3D-pharmacophore model generation and virtual screening: identification of potential PfDHFR inhibitors

“…As described in previous sections, the identified hits show all the necessary interactions in the active site which are required by antifolate PfDHFR inhibitors for effective inhibition of this enzyme 6,7,11,18,25 . Their hydrogen bond donor features interact with Asp54 and Ile14 or/and Leu164, whereas the hydrophobic portions interact with amino acid residues Met55, Ser111, Pro113, and other amino acids via hydrophobic interactions.…”

“…The hits were selected based on their docking scores, binding orientations, and interactions with key amino acid residues in the active site (Asp54, Ile14, and Leu164) as well as their interactions in the hydrophobic region of the active site. Because of the flexible nature of their side chains, there are no potential steric clashes with Asn108, which is known to be responsible for resistance of the mutant parasite to antimalarial drugs 1 and 2 6,7,[10][11][12][13]18,25 . The hits also fulfill all the properties required by drug-like molecules 47,48 .…”

“…This results in the development of resistance of the parasite to 2. On the other hand, in the case of a multiplemutant parasite, steric clashes of the para-Cl groups of both 1 and 2 with Asn108 (mutated from Ser108) result in the loss of inhibitory activities of these drugs or increase the chance of the parasite to develop cross-resistance compounds which are more flexible than 1 and 2 could avoid steric clashes, and subsequently result in agents that effectively inhibit mutant PfDHFRs 7,[12][13][14][15][16][17][18] . WR99210 (3) is one of the typical examples of compounds designed to avoid steric clash with Asn108 of the mutant PfDHFR enzyme (Figure 1).…”