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SPD‐304 was discovered as a promising tumor necrosis factor alpha (TNF) antagonist that promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. However, SPD‐304 contains a potentially toxic 3‐alkylindole moiety, which can be bioactivated to a reactive electrophilic intermediate. A series of SPD‐304 analogs was synthesized with the aim to diminish its toxicophore groups while maintaining the binding affinity for TNF. Incorporation of electron‐withdrawing substituents at the indole moiety, in conjunction with elimination of the 6′‐methyl group of the 4‐chromone moiety, led to a significantly less toxic and equally potent TNF inhibitor.