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. 2022 Mar 1:59:128546.
doi: 10.1016/j.bmcl.2022.128546. Epub 2022 Jan 12.

Antischistosomal tetrahydro-γ-carboline sulfonamides

Rongguo Ren  1 , Xiaofang Wang  1 , Derek A Leas  1 , Cécile Häberli  2 , Monica Cal  2 , Yuxiang Dong  1 , Marcel Kaiser  2 , Jennifer Keiser  2 , Jonathan L Vennerstrom  3
Affiliations

Antischistosomal tetrahydro-γ-carboline sulfonamides

Rongguo Ren et al. Bioorg Med Chem Lett. .

Abstract

We discovered tetrahydro-γ-carboline sulfonamides as a new antischistosomal chemotype. The aryl sulfonamide and tetrahydro-γ-carboline substructures were required for high antischistosomal activity. Increasing polarity improved solubility and metabolic stability but decreased antischistosomal activity. We identified two compounds with IC50 values <5 µM against ex vivo Schistosoma mansoni.

Keywords: Antischistosomal; SAR; Sulfonamides; Tetrahydro-γ-carboline.

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Figures

Figure 1.
Figure 1.
Witkop oxidation of 1 by ozonolysis.
Scheme 1.
Scheme 1.
Reagents and conditions: (a) O3, 4:1 DCM/MeOH, −78 °C, 10 min, then Me2S, −78 °C to rt, 2 h; (b) bromoacetamide, NaH, DMF, 0 °C to rt, 24 h;
Scheme 2.
Scheme 2.
Reagents and conditions: (a) 1-fluoro-4-isocyanatobenzene, DCM, 0 °C to rt, 24 h; (b) (4-fluorophenyl)methanesulfonyl chloride, Et3N, DCM, Ar, 0 °C to rt; 24 h; (c) 4-fluorobenzenesulfonyl chloride, Et3N, DCM, Ar, 0 °C to rt; 24 h.
Scheme 3.
Scheme 3.
Reagents and conditions: (a) Et3N (2N aq. NaOH – 63) DCM, Ar, 0 °C to rt; 24 h.
Scheme 4.
Scheme 4.
Reagents and conditions: (a) Et3N (1N aq. NaOH – 19), DCM, Ar, 0 °C to rt; 24 h; (b) morpholine, HOBT, N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDCI), Et3N dimethylacetamide, rt, 24 h; (c) 28% wt. NH4OH, rt, 12 h.
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