Structure-activity relationships of 1,5-dihydro-2 H-benzo[ b][1,4]diazepine-2,4(3 H)-diones as inhibitors of Trypanosoma cruzi

Abstract

Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi), is responsible for a large health burden with around 6-8 million people infected globally. The current drug development pipeline is sparsely populated and there is an urgent need for new treatments. In this paper we describe the identification of a series of benzodiazepinediones with antiparasitic activity, and the platform we utilised to demonstrate that they act via a novel mechanism of action. Two distinct sub-series were identified, and the medicinal chemistry program identified compounds from both with pIC₅₀'s >6.4 which were progressed to a T. cruzi washout assay. This assay showed that neither sub-series was suitable for further development. This work demonstrated the value of a robust Chagas disease discovery platform for focusing the limited resources available for neglected disease drug discovery onto the most promising series.

Fig. 1. Screening cascade for the identification of compound series for progression against T. cruzi. ^aSelectivity refers to T. cruzi vs. Vero activity in the cell-based T. cruzi assay.

Fig. 2. GSK2982772 (12).

Fig. 3. Plot of T. cruzi antiparasitic activity vs. Tc-CYP51 activity: blue compounds represent the original urea series; red compounds represent the primary amino sub-series. Black line is equipotency line, green line = 10-fold higher potency against CYP51, blue line = 10-fold higher potency against intracellular T. cruzi parasites. Dose response curves can be found in ESI1.

Scheme 1. Reagents and conditions: (i) NaH, RT, DMF (25c, 25d, 25h), K₂CO₃, 130 °C, DMF (25f, 25g) or NEt₃, 90 °C, DMF (25i), 16 h, 55–96%; (ii) Fe powder with NH₄Cl or HCl, EtOH/water, reflux (26c, 26d, 26f, 26g, 26k), or Zn, AcOH (26h, 26i), 1 h, 82–93%; (iii) 4-OMe-benzoyl chloride, NEt₃, DCM, RT, 2 h, 13–96%; (iv) LiAlH₄, THF, RT, 1.5 h, 19–89%; (v) 29, THF, RT, 2 h, 8–99%; (vi) Zn, AcOH, 0–25 °C (31a–e, 31g, 18, 19, 22) or 10% Pd–C, H₂, MeOH (31f, 17), 12–20 h, 13–90%; (vii) CAN, MeCN, 0–25 °C, 16 h, 26–79%; (viii) relevant isocyanate, DCM, RT, 1–12 h, 11–87%; (ix) malonyl dichloride, THF, 14 h, 16%.

Scheme 2. Reagents and conditions: (i) X = N K₂CO₃, EtOH, 90 °C, 16 h, 70% (33a); X = O NaH, THF, RT, 16 h, 45% (33b); (ii) Fe, NH₄Cl, EtOH/THF/water, reflux, 1 h, 90%; (iii) HBTU, NEt₃, DMF, RT, 2 h, 15–26%; (iv) PhBr, Pd₂dba₃, Xantphos, 80 °C, 16 h, 61–71%; (v) TFA or HCl, DCM, RT, 2 h, 66–68% then 4-methylbenzeneisocyanate, NEt₃, DCM, RT, 2 h, 25–78%; (vi) TFAA, DIPEA, DCM, RT, 2 h, 72%; (vii) PhI, CuI, K₂CO₃, dioxane, 100 °C, 16 h, 66%; (viii) K₂CO₃, MeOH, RT, 2 h, 25%.