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. 2023 Feb 9;66(3):1972-1989.
doi: 10.1021/acs.jmedchem.2c01767. Epub 2023 Jan 25.

Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

Baljinder Singh  1 , Amrita Sharma  2 , Naresh Gunaganti  1 , Mitch Rivers  1 , Pradip K Gadekar  1 , Brady Greene  1 , Michael Chichioco  1 , Carlos E Sanz-Rodriguez  3 , Courtney Fu  1 , Catherine LeBlanc  1 , Erin Burchfield  1 , Nyle Sharif  1 , Benjamin Hoffman  3 , Gaurav Kumar  2 , Andrei Purmal  4 , Kojo Mensa-Wilmot  2   3 , Michael P Pollastri  1
Affiliations

Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

Baljinder Singh et al. J Med Chem. .

Abstract

The carbazole CBL0137 (1) is a lead for drug development against human African trypanosomiasis (HAT), a disease caused by Trypanosoma brucei. To advance 1 as a candidate drug, we synthesized new analogs that were evaluated for the physicochemical properties, antitrypanosome potency, selectivity against human cells, metabolism in microsomes or hepatocytes, and efflux ratios. Structure-activity/property analyses of analogs revealed eight new compounds with higher or equivalent selectivity indices (5j, 5t, 5v, 5w, 5y, 8d, 13i, and 22e). Based on the overall compound profiles, compounds 5v and 5w were selected for assessment in a mouse model of HAT; while 5v demonstrated a lead-like profile for HAT drug development, 5w showed a lack of efficacy. Lessons from these studies will inform further optimization of carbazoles for HAT and other indications.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structure of 1 and synthesis strategies employed.
Scheme 1
Scheme 1. Synthetic Route for Compounds 5a–ab
Reagents and conditions: (a) acetyl chloride, AlCl3, dichloromethane, 0 °C to room temperature (rt), 48 h; (b) dibromoethane, NaH, dimethylformamide (DMF), 60 °C, 40 min; (c) 2-bromoethyl 4-methylbenzenesulfonate, Cs2CO3, DMF, rt, 16 h; (d) amine, iso-propyl alcohol (IPA), microwave 100 °C, 30–90 min; (e) amine, DMF, microwave 100 °C, 30 min; and (f) trifluoroacetic acid (TFA), dichloromethane, rt, 1 h.
Scheme 2
Scheme 2. Synthetic Route for Compounds 5ac–al
Reagents and conditions: (a) 2-bromoethanol, Cs2CO3, DMF, 60 °C, 16 h; (b) Dess–Martin periodinane, acetonitrile (ACN), 80 °C, 80 min; and (c) amine, acetic acid, sodium triacetoxyborohydride, dichloroethane, molecular sieves, rt, 2.5 h.
Scheme 3
Scheme 3. Synthetic Route for Compounds 9
Reagents and conditions: (a) 2-(2-bromoethoxy)propane, Cs2CO3, DMF, rt, 16 h.
Scheme 4
Scheme 4. Synthetic Route for Compounds 12
Reagents and conditions: (a) 2-bromoethyl 4-methylbenzenesulfonate, Cs2CO3, DMF, rt, 16 h; (b) isopropylamine, DMF, microwave 100 °C, 30 min; (c) boronic acid/ester, Pd2dba3, PCy3, K2CO3, DMF/water (3:1), microwave, 130 °C, 3 h; (d) amine, Pd2dba3, t-BuXPhos, potassium 2-methylpropan-2-olate, dioxane, microwave, 110 °C, 35 min; and (e) 4.0 M HCl in dioxane, rt.
Scheme 5
Scheme 5. Synthetic Route for Compound 15
Reagents and conditions: (a) Zn(CN)2, Zn, Zn(OAc)2·2H2O, DMF/water (100:1), 100 °C, 20 h; (b) 2-bromoethyl 4-methylbenzenesulfonate, Cs2CO3, DMF, rt, 16 h; and (c) isopropylamine, DMF, microwave 100 °C, 30 min.
Scheme 6
Scheme 6. Synthetic Route for Compounds 21
Reagents and conditions: (a) Pd(OAc)2, Xantphos, Cs2CO3, dioxane, 100 °C, 16 h; (b) Pd(OAc)2, (±)-BINAP, Cs2CO3, toluene, microwave 130 °C, 3 h; (c) Pd(OAc)2, Xphos, Cs2CO3, toluene, 130 °C, 1 h; (d) Pd(OAc)2, K2CO3, pivalic acid, 100 °C, air, 16 h; (e) 2-bromoethyl 4-methylbenzenesulfonate, Cs2CO3, DMF, rt, 16 h; and (f) amine, DMF, microwave 100 °C, 30 min.
Scheme 7
Scheme 7. Synthetic Route for Compound 22
Reagents and conditions: (a) methoxyamine hydrochloride, ethanol, rt, 18 h.
Figure 2
Figure 2
Key SAR and SPR points around this series for anti-T. brucei activity (1).
Scheme 8
Scheme 8. Synthetic Route for Compound 26
Reagents and conditions: (a) 2-bromoethyl 4-methylbenzenesulfonate, Cs2CO3, DMF, rt, 16 h; and (b) amine, DMF, microwave 100 °C, 30 min.
Figure 3
Figure 3
Delayed cytocidal concentrations (DCCs) of 5v and 5w. T.b. brucei (1 × 105/mL HMI-9 medium) was treated with serial concentrations of 5v or 5w in 24-well plates. After 6 h, cells were washed with and transferred into a drug-free HMI-9 medium for 48 h at a starting cell density of 1 × 104 trypanosomes/mL. At the end of 48 h, trypanosomes were enumerated with a hemocytometer. Nonlinear regression graphs were constructed in GraphPad Prism to obtain DCC50 values.
Figure 4
Figure 4
Efficacy of 5v and 5w in a mouse model of chronic HAT. Mice (n = 4 per group) were infected with T. brucei AnTat1.1 AmLuc (5 × 104). Trypanosome infection of mice was confirmed on day 0 by the detection of bioluminescence signals in all mice (data not shown). Compound 5v was administered to mice B1–B4 (80 mg/kg on days 1, 2, 3, 4, 7, 8, 9, 10, 13, and 14 post infection). Compound 5w was administered to mice C1–C4 (80 mg/kg on days 1, 2, 3, 4, 5, 8, 9, 10, 11, and 12 post infection). Control mice (A1–A4) received vehicle (5% NMP in 0.2% HPMC) for 10 days. For imaging, mice were injected with D-luciferin (150 mg/kg) and bioluminescence signal obtained after 12 min using an IVIS Lumina II. Images of mice were obtained at 60 s exposures. (A) Montage of infected vehicle-treated (A1–A4), infected 5v-treated (B1–B4), and infected 5w-treated (C1–C4) mice on different days post infection. Mice A4 and B2 died during the course of the study due to unknown causes. (B) Bioluminescence signal intensity from whole mice is presented; the bar indicates mean values. The statistical significance of differences in the total flux between untreated and drug-treated mice was analyzed with a t-test (Prism 5.0 software).
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