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. 2018 Nov 7;9(12):1235-1240.
doi: 10.1021/acsmedchemlett.8b00389. eCollection 2018 Dec 13.

Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance

Bongkoch Tarnchompoo  1 , Penchit Chitnumsub  1 , Aritsara Jaruwat  1 , Philip J Shaw  1 , Jarunee Vanichtanankul  1 , Sinothai Poen  1 , Roonglawan Rattanajak  1 , Chayaphat Wongsombat  1 , Aunchalee Tonsomboon  1 , Sasithorn Decharuangsilp  1 , Tosapol Anukunwithaya  1 , Uthai Arwon  1 , Sumalee Kamchonwongpaisan  1 , Yongyuth Yuthavong  1
Affiliations

Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance

Bongkoch Tarnchompoo et al. ACS Med Chem Lett. .

Abstract

The S108N mutation of dihydrofolate reductase (DHFR) renders Plasmodium falciparum malaria parasites resistant to pyrimethamine through steric clash with the rigid side chain of the inhibitor. Inhibitors with flexible side chains can avoid this clash and retain effectiveness against the mutant. However, other mutations such as N108S reversion confer resistance to flexible inhibitors. We designed and synthesized hybrid inhibitors with two structural types in a single molecule, which are effective against both wild-type and multiple mutants of P. falciparum through their selective target binding, as demonstrated by X-ray crystallography. Furthermore, the hybrid inhibitors can forestall the emergence of new resistant mutants, as shown by selection of mutants resistant to hybrid compound BT1 from a diverse PfDHFR random mutant library expressed in a surrogate bacterial system. These results show that it is possible to develop effective antifolate antimalarials to which the range of parasite resistance mutations is greatly reduced.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Designs of inhibitors that can automatically modulate their binding modes to suit the catalytic sites which they encounter. (A) Structures of representative DHFR inhibitors. Pyr and P30 are rigid inhibitors, whereas P65 is a flexible inhibitor. (B) Our design of the dual binding mode DHFR hybrid inhibitors. The rigid part, represented by Pyr derivative, is joined with a flexible diaminopyrimidine moiety. (C) Structures of hybrid inhibitors synthesized in this study.
Scheme 1
Scheme 1. Synthesis of Hybrid Inhibitors: (A) Rigid–Flexible Hybrid and (B) Rigid–Rigid Hybrid
Reagents and conditions: (a) CH2N2, dioxane-MeOH; (b) guanidine, DMSO-MeOH, 90–100 °C; (c) cyclohexene, Pd/C, 65 °C; (d) Ph3P, DIAD, DMF, rt; (e) HCl, H2O.
Figure 2
Figure 2
Inhibition modes of hybrid inhibitors in PfDHFR. Detailed interactions of (A) BT1, (B) BT2, and (C) BT3 with wild-type PfDHFR, quadruple mutant PfDHFR, and superposition of wild-type and quadruple mutant PfDHFRs. Displacement of NADPH was observed in quadruple mutant due to steric clash with S108N upon binding of BT3. Inhibitors and key amino acids are shown as a stick model. Important interactions are highlighted as dashed lines in black, and π–π interaction is drawn as a double dashed line.
Figure 3
Figure 3
Superposition of cocomplex BT1, BT2, and BT3 structures of PfDHFRs. (A) Wild-type PfDHFR. (B) Quadruple mutant PfDHFR. The nicotinamide ring of NADPH was perturbed by the binding of the hybrid inhibitors to different levels in quadruple mutant PfDHFR structures, while insignificant displacement of NADPH occurred in wild-type. The most severe perturbation of the NADPH was observed with the binding of BT3, which coincided with the displacement of S108N side chain.
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