Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities - PubMed (original) (raw)

doi: 10.1016/j.rechem.2024.101890. Epub 2024 Nov 6.

John Sichinga 1, Harrison Banda 1, Steve Mbaya 1, Evelyn Funjika 1, Godfrey Mayoka 2, Christabel Hikaambo 3, Karol R Francisco 4, Yujie Uli Sun 4, Lawrence J Liu 4, Conor R Caffrey 4, Peter Mubanga Cheuka 1

Affiliations

Structure activity relationships of antischistosomal _N_-phenylbenzamides by incorporation of electron-withdrawing functionalities

Ameera Mohammed Dawoodjee et al. Results Chem. 2024 Dec.

Abstract

For the adult Schistosoma mansoni flatworm pathogen, we report further structure activity relationships (SAR) of 19 _N_-phenylbenzamide analogs. Our previous SAR studies, designed by selecting representative substituents from the Craig plot, identified 9 and 11 which possessed electron-withdrawing groups that benefited potency. This study sought to enhance the potency of this chemotype by incorporating other electron-withdrawing functionalities not studied previously and to overcome the potential pharmacokinetic liabilities associated with the high lipophilicity of frontrunner compounds. Compared to the most potent compound, 9 (EC50 = 80 nM), from our previous work, the most potent compounds in the current study (32 (EC50 = 1.17 μM), 34 (EC50 = 1.64 μM) and 38 (EC50 = 1.16 μM)) were less active although they retained single digit micromolar potency. Furthermore, compound 38 generated a CC50 value of > 20 μM in counter toxicity screens using HEK 293 cells, translating to a wide selectivity index of > 17.

Keywords: N-phenylbenzamide analogs; N-pyridazinylbenzamide analogs; Schistosoma mansoni.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.

Fig. 1.

Structures of compounds 1, 9 and 11.

Scheme 1.

Scheme 1.

Reagents and conditions: (a) (i) EDCI, DMAP, DCM, 0 °C, 30 min; (ii) substituted aniline (or pyridazinamines for c5 – c10), 25–30 °C (or room temperature for c5 – c10), 2–24 h (all analogs except 41–43) or (b) (i) DCC, DMAP, DCM, 0 °C, 20 min; (ii) _m_- or _o-_nitroaniline (41–43), 30–33 °C, 24–26 h.

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