7-(3-Chlorophenylamino)-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid

Abstract

7-(3-Chlorophenylamino)-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (2) was prepared and fully characterized by NMR, IR, and MS. Compound 2 exhibited good antibacterial activity against gram-positive standard and resistant strains.

1. Introduction

To date, fluoroquinolones represent successful synthetic antibacterial agents [1,2,3,4,5]. However, increased prescribing has led to the recent emergence of fluoroquinolone-resistant bacteria which has necessitated the search for newer drugs with efficacy against resistant strains [6,7]. The present work aims at the synthesis of a new fluoroquinolone derivative (2) and screening of its activity.

2. Results and Discussion

An earlier study carried out by our team [4] revealed that substitution of lipophilic groups such as aniline at C-7 of 8-nitrofluoroquinolone (1) produced noticeable increase in gram-positive activity, especially against resistant strains with significant loss of gram-negative activity [4]. This research aims at further investigation of halogenated aniline derivatives exemplified by compound 2. Synthon 1 involved introducing an electron-withdrawing nitro group at C-8 to facilitate coupling of the chloroaniline [4]. Although compound 2 was prepared by direct coupling of 7-chloro-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1b) with a 2 molar excess of 3-chloroaniline in DMF/pyridine (7:3 V/V), the yield was very low after chromatographic separation from many side products. Alternatively, the chloroaniline was reacted with the correspondent ester (1a) to produce the target acid 2 in satisfactory yield upon hydrolysis of the ester intermediate (Scheme 1).

The in vitro antibacterial activity of 2 was evaluated against standard and resistant isolates of gram-positive Staphylococcus aureus and gram-negative Escherichia coli bacteria, using broth dilution method. Compound 2 revealed excellent antimicrobial activity against standard S. aureus strains (ATCC6538) with minimum inhibitory concentrations (MIC) of 0.88 µg/mL. Interestingly, it showed good activity against resistant isolates of S. aureus gram-positive bacteria with MIC value of 7.0 µg/mL. These data are comparable to ciprofloxacin reference which showed MIC values of 2.9 µg/mL and 1.4 µg/mL, respectively, against both gram-positive strains.

These findings are in correlation with literature findings that more lipophilic quinolones can better penetrate the lipophilic cell membrane of gram-positive bacteria [8,9].

3. Experimental

Two molar equivalents of 3-chloroaniline (0.36 g) were gradually added to a solution of ethyl 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1a) (0.5 g) in 10 mL of DMSO and a few drops of pyridine. The mixture was heated at 70–80 °C under anhydrous conditions. The reaction mixture was left to crystallize, then filtered and the product was left to dry in a dark place. The resulting solid was recrystallized from methanol/chloroform (3x) to give fairly pure ester intermediate (0.15 g, 24%). The intermediate was then hydrolyzed upon dissolving the solid in ethanol and adding conc. HCl (10 mL). The mixture was heated at 70–80 °C for 5 h, then compound 2 was collected by filtration and dried to give a yellow solid (0.13 g, 93%).

M.p.: 240–243 °C (decomp).

IR (KBr, cm⁻¹): ν 3434, 3390, 2942, 1735, 1640, 1535, 1467, 1365, 1210, 1225.

¹H-NMR (300 MHz, DMSO-d₆): δ 0.95, 1.02 (2m, 4H, H₂-2′/H₂-3′), 3.71 (m, 1H, H-1′), 7.16 (dd, J = 1.0, 7.8 Hz, 1H, Ar-H), 7.39 (dd, J = 7.8, 8.1 Hz, 1H, Ar-H), 7.49 (d, J = 8.4 Hz, 1H, Ar-H), 7.98 (m, J_H5-F = 11.2 Hz, 2H, Ar-H and H-5), 8.50 (br s, 1H, NH, D₂O exchangeable), 8.76 (s, 1H, H-2), 12.95 (br s, 1H, CO₂H).

MS (CI/ESI-ve): m/z (% rel. int.): calcd. for C₁₉H₁₃ClFN₃O₅ (417.8): 419 (5), 418 (34), 417 (21), 416 (78), 383 (4), 360 (5), 359 (35), 339 (7), 325 (6), 311 (8), 293 (12), 265 (100), 191 (6), 161 (6).

Elemental Analysis: Calcd. for C₁₉H₁₃ClFN₃O₅, C, 54.62; H, 3.14; N, 10.06. Found: C, 54.61; H, 3.20; N, 9.97.