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. 2022 Aug 25;65(16):11388-11403.
doi: 10.1021/acs.jmedchem.2c00960. Epub 2022 Aug 16.

Discovery of Substituted Di(pyridin-2-yl)-1,2,4-thiadiazol-5-amines as Novel Macrofilaricidal Compounds for the Treatment of Human Filarial Infections

Natalie Hawryluk  1 , Dale Robinson  1 , Yixing Shen  1 , Graham Kyne  2 , Matthew Bedore  2 , Sanjay Menon  2 , Stacie Canan  1 , Thomas von Geldern  3 , Simon Townson  4 , Suzanne Gokool  4 , Alexandra Ehrens  5   6 , Marianne Koschel  5 , Nathaly Lhermitte-Vallarino  7 , Coralie Martin  7 , Achim Hoerauf  5   6 , Geraldine Hernandez  1 , Deepak Dalvie  1 , Sabine Specht  5   8 , Marc Peter Hübner  5   6 , Ivan Scandale  8
Affiliations

Discovery of Substituted Di(pyridin-2-yl)-1,2,4-thiadiazol-5-amines as Novel Macrofilaricidal Compounds for the Treatment of Human Filarial Infections

Natalie Hawryluk et al. J Med Chem. .

Abstract

Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting about 145 million people worldwide. Efforts to control and eliminate onchocerciasis are impeded by a lack of effective treatments that target the adult filarial stage. Herein, we describe the discovery of a series of substituted di(pyridin-2-yl)-1,2,4-thiadiazol-5-amines as novel macrofilaricides for the treatment of human filarial infections.

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Conflict of interest statement

The authors declare the following competing financial interest(s): The contents are the responsibility of the Drugs for Neglected Diseases initiative and do not necessarily reflect the views of the donors. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NAH, DR and SC are former employees of BMS, YS, GH and DD are employees of BMS. GK, MB and SM are employees of Zoetis. NAH, DR, SC, GH, and DD are BMS shareholders and GK, MB and SM are Zoetis shareholders with no other competing interest. All other authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1
Initial amino thiazole hit molecule, 1, and lead optimization progression to a novel scaffold.
Scheme 1
Scheme 1. Synthesis of Di(pyridin-2-yl)-1,2,4-thia-diazol-5-amine and Di(pyridin-2-yl)-1,2,4-oxa-diazol-5-amine
Reagents and conditions: (a) K2CO3, THF, 0–25 °C, 16 h, 70–92%, (b) (II), DMSO, KOtBu, 25 °C, 16 h 12–72%, (c) Et3N, DCM/acetone, 15 °C, 2 h, 17–49%, (d) I2, H2O2, EtOH, 25 °C, 1 h, 14–70%, (e) thiophosgene, DCM, 0 °C, 1 h, 66%, (f) MeI or iPr-I, nBuLi, THF, −70 °C, 1–16 h, 31–75% (g) NaOMe, MeOH, 15 °C, 14 h, (h) NH4Cl, 70 °C, 2 h (39–93% for panels (g, h)), (i) NH2OH HCl, Et3NH2, EtOH, 80 °C, 16 h, (j) (Cl3CO)2O, toluene, 110 °C, 16 h. (65–97% for panels (i, j)), (k) NaH, THF, 25 °C, 30 min, 12–25%.
Scheme 2
Scheme 2. Synthesis of Di(pyridin-2-yl)-1,3,4-thia-oxa-diazol-5-amine and Di(pyridin-2-yl)-1,2,4-triazol-5-amine
Reagents and conditions: (a) SOCl2, MeOH, 10–70 °C, 3 h, (b) N2H2 H2O, MeOH, 70 °C, 92%, 10 h, (c) (III), DCM, 30 °C, 19 h, 16–38% (d) pTsOH, toluene, 100 °C, 6 h, 32–51%, (e) DMSO, EDCI, 60 °C, 2 h, 24–35%, or IBX, DCM, Et3N, 0 °C, 1 h, 7%, (f) NH4OH, DCM, 30 °C, 1 h, 53%, (g) MeI, CH3CN, 40 °C, 16 h, 41%, (h) pyridine, 120 °C, 16 h, 10–29%.
Figure 2
Figure 2
Adult worm burden in L. sigmodontis-infected female BALB/c mice and jirds after oral treatment with the candidates. Shown is the adult worm burden at 63–78 days after infection as mean plus standard deviation from the treatment groups and vehicle controls. (A) Mice have been naturally infected with L. sigmodontis for 35–37 days post infection and then treated orally. (B) Mice were subcutaneously infected with 40 infective L3 L. sigmodontis larvae and treated orally for 30–33 days post infection. (C) Jirds were subcutaneously infected with 40 infective L3 L. sigmodontis larvae and treated orally for 35–42 days post infection. Flubendazole (FBZ) was administered in all experiments subcutaneously (SC). Analysis was done using the unpaired two-tailed t test with n = 5–8 animals per group; FBZ was given to three to four animals.
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