N -Acylated Derivatives of Sulfamethoxazole and Sulfafurazole Inhibit Intracellular Growth of Chlamydia trachomatis

Abstract

f Antibacterial compounds with novel modes of action are needed for management of bacterial infections. Here we describe a high-content screen of 9,800 compounds identifying acylated sulfonamides as novel growth inhibitors of the sexually transmitted pathogen Chlamydia trachomatis. The effect was bactericidal and distinct from that of sulfonamide antibiotics, as para-aminobenzoic acid did not reduce efficacy. Chemical inhibitors play an important role in Chlamydia research as probes of potential targets and as drug development starting points.

Design, synthesis and evaluation of novel polypharmacological antichlamydial agents

“…1) [12] to explore if the antichlamydial activity could be improved. The salicylidene acylhydrazide pharmacophore D in compound I is responsible for both iron chelation [9,17] and T3S inhibition [18] and by combination with the core and extended scaffolds B and C in the antichlamydial compounds II (Fig.…”

“…The salicylidene acylhydrazide pharmacophore D in compound I is responsible for both iron chelation [9,17] and T3S inhibition [18] and by combination with the core and extended scaffolds B and C in the antichlamydial compounds II (Fig. 1) [12] we envisioned that the resulting compounds 11aed and 15aed would maintain all three biological activities. The specific building blocks and substitution patterns as well as the positions for merging the different structural elements were selected based on previous structureeactivity relationships the identified positions that allow substantial structural variation [12,18,19].…”

“…1) [12] we envisioned that the resulting compounds 11aed and 15aed would maintain all three biological activities. The specific building blocks and substitution patterns as well as the positions for merging the different structural elements were selected based on previous structureeactivity relationships the identified positions that allow substantial structural variation [12,18,19].…”

“…The intermediate N-(4-(N-(5-methylisoxazol-3-yl)sulfamoyl)phenyl)acetamide 2 (59%) was obtained by reacting 4-acetamidobenzene-1-sulfonyl chloride 1 with 5-methylisoxazol-3-amine in pyridine, which was subjected for deacetylation with NaOH to achieve 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide 3 in 93% yield [12]. Compound 3 was then reacted with triphosgene to form the corresponding isocyanate that subsequently was combined with different amines to obtain the urea compounds 4aed in 16e30% yields.…”

“…1) and N-(phenylcarbamothioyl)-1-naphthamides III (Fig. 1) as potent inhibitors of Chlamydiae [12]. In addition, recent literature describe urea and thiourea derivatives as inhibitors of gram-negative bacteria [13e16].…”