Abstract
A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC50 of 1.57 ± 0.11 nM and a hDHFR to TgDHFR selectivity ratio of 196, making it 89-fold more potent and 16-fold more selective than 1. Compound 3 was highly effective in control of acute infection by highly virulent strains of T. gondii in the murine model, and it possesses the best combination of selectivity, potency, and prerequisite drug-like properties to advance into IND-enabling, preclinical development.
Highlights
Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii (T. gondii), an obligate intracellular parasite capable of infecting a wide range of hosts and many different types of cells.[1]
We report on the Structure−activity relationship (SAR) and lead optimization strategy underlying the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3, a selective and potent Toxoplasma gondii DHFR (TgDHFR) inhibitor with properties consistent with those outlined above supporting the first standalone treatment for toxoplasmosis
Pyrimethamine 1 is reported to be 7.6-fold more selective for TgDHFR compared to hDHFR with a hDHFR IC50 of 760 ± 130 nM for inhibiting conversion of dihydrofolate to tetrahydrofolate.[31]
Summary
Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii (T. gondii), an obligate intracellular parasite capable of infecting a wide range of hosts and many different types of cells.[1]. The parasitic infection is kept in check by the immune system where it exists in a latent bradyzoite form contained within tissue cysts that are commonly found in skeletal muscle and the central nervous system (CNS).[4] in cases where the immune system is compromised, such as in a developing fetus or in patients with HIV, undergoing cancer chemotherapy or immunosuppressive treatment for organ transplantation, the parasite can transition to an active, fast replicating, and tissue damaging tachyzoite form.[5] Depending upon localization of the tachyzoites, active infection can cause, among other conditions, myocarditis, blindness, and encephalitis and is associated with a high mortality rate for HIV patients, even for those on active antiretroviral treatment.[5−8]
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