Quinolone-3-amidoalkanol: A New Class of Potent and Broad-Spectrum Antimicrobial Agent

Abstract

Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-positive and -negative bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities (<1 μg/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compounds in this study are metabolically robust, demonstrating % remnant of >98% after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.

Figure 1

Previously identified hit compounds.

Figure 2

Synthetic plan to generate analogues for SAR.

Scheme 1. Synthesis of Target Compounds

Reagents and conditions: (i) benzyl halide, K₂CO₃, acetone, reflux 12 h; (ii) Fe-powder, acetic acid, NH₄Cl, ethanol, reflux 12–48 h; (iii) ethanol, reflux 12 h; (iv) diphenyl ether, 240–250 °C, 15 min; (v) K₂CO₃, CHCl₃/THF (2:1), benzyl/alkyl halide (3 equiv), reflux, 36 h; (vi) amine (5 equiv), DBU (1.5 equiv), CHCl₃, reflux 48–72 h.

Figure 3

Summary of antitubercular SARS.