New N -4 piperazinyl derivatives of norfloxacin: design, synthesis, and correlation of calculated physicochemical parameters with antibacterial activity

Abstract

A group of N − 4 piperazinyl derivatives of norfloxacin was synthesized and identified by different spectroscopic techniques. The N − 4 piperazinyl substituent in target compounds 2a-2k, 3a-3c, and 4a and 4b was designed to have different electronic, steric, and physicochemical properties. The antibacterial activity of the newly synthesized compounds was evaluated against Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus strains using norfloxacin as a reference. Results showed that most of the tested compounds had higher activity against E. coli and K. pneumoniae than norfloxacin, whereas only five derivatives were more active against P. aeruginosa. On the other hand, all derivatives were less active than norfloxacin against S. aureus. The biological activity of the target compounds, expressed in log MIC, is correlated with lipophilicity, polarizability, and topology parameters. Results showed that none of the calculated parameters could determine the biological activity. Consequently, the total volume of the molecule, bulkiness at C-7, electronic factors, and lipophilicity are important factors that should be considered in the design of new fluoroquinolones.

Design, Synthesis, Molecular Modeling, Biological Activity, and Mechanism of Action of Novel Amino Acid Derivatives of Norfloxacin

“…In addition, glycine ethyl ester compounds 4a, 4c–e showed triplet signals at δ 1.41–1.26 ppm assigned to CH 3 CH 2 OOC and quartet signals at δ 4.15–4.12 ppm assigned to CH 3 CH 2 OOC, which overlapped with the doublet signal assigned to NH CH 2 CO. For the serine methyl ester compounds 4b and 4f , we observed singlet signals at δ 3.78–3.10 ppm assigned to COO CH 3 and a triplet peak at δ 5.24 assigned to CH 2 OH . Other signals, including aromatic protons, appeared at their expected chemical shift in agreement with the reported data. , In the case of the hydrazide compounds 5a – e , IR spectra showed absorption bands at 3315, 1693, 1669, and 1610 cm –1 assigned to NH, hydrazide CO, carbamidic CO, and quinolone CO groups, respectively. In addition to the expected aromatic and characteristic protons of their parent compounds 4a – e , the 1 HNMR spectra of the hydrazides 5a – e were also characterized by the disappearance of ester group signals, the presence of triplet or doublet (in the case of serine amino acid) signals at δ 10.32–10.17 ppm assigned to amidic CO NH , broad singlet signals at δ 9.19–9.13 ppm assigned to NH 2 NH of hydrazide, and a singlet signal at δ 4.23 ppm assigned to NH NH 2 of hydrazide.…”

“…Other signals, including aromatic protons, appeared at their expected chemical shift in agreement with the reported data. 21,22 In the case of the hydrazide compounds 5a−e, IR spectra showed absorption bands at 3315, 1693, 1669, and 1610 cm −1 assigned to NH, hydrazide C�O, carbamidic C�O, and quinolone C�O groups, respectively. In addition to the expected aromatic and characteristic protons of their parent compounds 4a−e, the 1 HNMR spectra of the hydrazides 5a−e were also characterized by the disappearance of ester group signals, the presence of triplet or doublet (in the case of serine amino acid) signals at δ 10.32−10.17 ppm assigned to amidic CONH, broad singlet signals at δ 9.19−9.13 ppm assigned to NH 2 NH of hydrazide, and a singlet signal at δ 4.23 ppm assigned to NHNH 2 of hydrazide.…”

“…A series of amino acid esters of N -acyl, sulfonyl, and alkyl derivatives of norfloxacin were synthesized, as outlined in Schemes and . Known acyl, sulfonyl, alkyl, and phenacyl derivatives 2a – f were synthesized according to published procedures. , Subsequently, amino acid ester derivatives 4a – f (Scheme , final yield 49–72%) were synthesized by the reaction of N-substituted piperazinyl norfloxacin derivatives with ethyl chloroformate in the presence of triethylamine in dichloromethane to afford mixed anhydrides, which then interacted with added amino acid ester hydrochloride. Finally, hydrazide derivatives 5a – e were prepared by the reaction of N -acyl norfloxacin amino acid esters with hydrazine hydrate in methanol (final yield 53–70%).…”

Rational design, synthesis, molecular modeling, biological activity, and mechanism of action of polypharmacological norfloxacin hydroxamic acid derivatives

“…Different acyl, sulphonyl, alkyl, or phenacyl norfloxacin derivatives 4–12 were synthesized as reported in the literature. 25,26 Hydroxamic acid derivatives 5–13 were synthesized by reaction of N 4-substituted piperazinyl norfloxacin derivatives with ethyl chloroformate in the presence of triethylamine in dichloromethane to afford a mixed anhydride, which then interacted with added hydroxylamine hydrochloride to afford hydroxamic acid in 53–84% yield. The final product was purified through crystallization with methanol and the obtained solid was triturated with diethyl ether.…”

Copper(I)‐Catalyzed Azide‐Alkyne Cycloaddition Microwave‐Assisted: Preparation of 7‐(4‐Substituted‐1H‐1,2,3‐Triazol‐1‐yl)‐Fluoroquinolones

“…[7,8] The most successful compounds developed are based on modifications at C-7, and it has been found that the spectrum, level of antibacterial activity, inhibition of DNA gyrase or topoisomerase IV, and cell permeability are highly affected by the nature of the C-7 substituent group. Substituents that have been studied included: medium-sized Nheterocyclic ring (5-and 6-membered), [9,10] N-substituted piperazine, [11,12] linear substituents with one or two heteroa-toms (-NHNH 2 , -NHR, -NHCH 2 CH 2 NH 2 ), methyl-, chloro-, and 1,2,3-triazole-derivatives. [13][14][15][16][17][18] The 1,2,3 moiety does not occur in nature, although the synthetic molecules containing 1,2,3triazole unit show diverse biological activities including antiobesity, antiallergic, antibacterial, antiparasitic, herbicidal, fungicidal, and anti-HIV.…”