Benzimidazole Isosteres of Salicylanilides Are Highly Active Colistin Adjuvants

Abstract

Multidrug-resistant bacterial infections have become a global threat. We recently disclosed that the known IKK-β inhibitor IMD-0354 and subsequent analogues abrogate colistin resistance in several Gram-negative strains. Herein, we report the activity of a second-generation library of IMD-0354 analogues incorporating a benzimidazole moiety as an amide isostere. We identified several analogues that show increased colistin potentiation activity against Gram-negative bacteria.

Exploring Structure–Activity Relationships of Niclosamide-Based Colistin Potentiators in Colistin-Resistant Gram-Negative Bacteria

“…Further modifying the amine with acylation (2) or alkylation to a complete loss of colistin-potentiating activity against both bacteria (Table 1). We next replaced the nitro group on niclosamide with an azide (4), a methy (5a), a carboxylic acid (6), various amide moieties (7)(8)(9)(10)(11)(12), and triazole fragments ( (Table 2). We observed that the azide and methyl ester derivatives retained synerg colistin against all strains tested, indicating that these modifications are compatibl the colistin potentiation of niclosamide.…”

“…Nonetheless, these findings demonstrated that the nitro gr mide can be replaced with a variety of substituents while still retaining sy istin. We next replaced the nitro group on niclosamide with an azide (4), a methyl ester (5a), a carboxylic acid (6), various amide moieties (7)(8)(9)(10)(11)(12), and triazole fragments (14-17) (Table 2). We observed that the azide and methyl ester derivatives retained synergy with colistin against all strains tested, indicating that these modifications are compatible with the colistin potentiation of niclosamide.…”

“…In order to further develop niclosamide as an adjuvant capable of augmenting colistin and overcome colistin resistance, new derivatives must be synthesized, and their structure-activity relationships need to be studied. Several publications have reported new niclosamide analogs for combating colistin resistance [12], as well as a detailed mechanistic understanding of niclosamide in combination with colistin [13].…”

6-Bromoindirubin-3′-oxime derivatives are highly active colistin adjuvants against Klebsiella pneumoniae

“…This set of analogues was synthesized following the route shown in Scheme 1, utilizing appropriately substituted indoles. Incorporation of a bromo substituent at the 5′- (22) or 6′- (23) position resulted in a moderate reduction in colistin potentiation (MICs of 4 and 8 μg mL −1 , respectively) in comparison to 5, while a bromo substituent at the 7′-position (24) resulted in comparable activity (1 μg mL −1 ). Incorporation of a chloro substituent at either 5′ (25), 6′ (26), or 7′ (27) also delivered…”

“…1). 22 Subsequent analog synthesis identified additional salicylanilide derivatives 23 as well as benzimidazole derivatives 24 (representative structures 6 and 7 ) that are more active than IMD-0354.…”