Piperazine Moiety Research Articles

Back Cover Image, Volume 78, Issue 4

The back cover image is based on the Research Article Ferulic acid derivatives with piperazine moiety as potential antiviral agents by Ting Yuan et al., https://doi.org/10.1002/ps.6794.image

Cinnamic acid derivatives linked to arylpiperazines as novel potent inhibitors of tyrosinase activity and melanin synthesis

A novel series of twenty-seven cinnamides constituted by cinnamic acid derivatives liked to 1-aryl piperazines were synthesized and evaluated for their potential inhibitory diphenolase activity of mushroom tyrosinase. Among them, the presence of a 3-chloro-4-fluorophenyl moiety at the N-1 position of piperazine ring was essential for a potent tyrosinase inhibitory effect, with the 3-nitrocinnamoyl (19p) and 2-chloro-3-methoxycinnamoyl (19t) derivatives as the most potent compounds of the series, with IC50 of 0.16 and 0.12 μM, respectively, resulting much active than kojic acid, whose IC50 value was 17.76 μM. In general, all compounds characterized by the presence of a 1-(3-chloro-4-fluorophenyl)piperazine moiety showed an excellent potency, and the nature, position and number of the substituents on the aryl of the cinnamic acid did not affect significantly the anti-tyrosinase activity. The molecular docking to the active site of the enzyme has been also performed to investigate the nature of enzyme-inhibitor interactions. Furthermore, for selected highly active compounds, their ability to inhibit melanogenesis in the A375 human melanoma cells and in vivo zebrafish model was also evaluated. One of the most potent compounds of series (19t) significantly reduced the pigmentation of zebrafish at 50 μM, unfortunately showing 100% mortality in the Fish Embryo Acute Toxicity (FET) test at the same concentration, Moreover, the zebrafish assay reveals that also compound 19r (IC50:0.51 μM against mushroom tyrosinase) effectively reduces melanogenesis with no acute toxicity effects and it could be proposed as potential candidate to treat tyrosinase-mediated hyperpigmentation.

Ferulic acid derivatives with piperazine moiety as potential antiviral agents.

Plant virus diseases are difficult to control and severely threaten the productivity of crops, which leads to huge financial losses. To discover the new antiviral drugs, 34 novel ferulic acid derivatives with piperazine moiety were synthesized, and the antiviral activities were systematically screened as well. Bioassay results indicated that most of the target compounds had outstanding antiviral activities against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) in vivo. In particular, compound E2 exhibited remarkable curative activities to TMV and CMV with EC50 values of 189.0 and 401.7μg/mL compared to those for ningnanmycin (387.0, 519.3μg/mL) and ribavirin (542.1, 721.5μg/mL). And then the mechanisms of compound E2 were studied by chlorophyll content, differentially expressed proteins and genes tests. The excellent antiviral activity of compound E2 was closely associated with the increase in host photosynthesis, which was confirmed by chlorophyll content, differentially expressed proteins and genes assays. Compound E2 can be considered as a lead structure for the discovery of new antiviral agents. © 2022 Society of Chemical Industry.

Synthesis and Characterization of Novel 2-Acyl-3-trifluoromethylquinoxaline 1,4-Dioxides as Potential Antimicrobial Agents.

The emergence of drug resistance in pathogens leads to a loss of effectiveness of antimicrobials and complicates the treatment of bacterial infections. Quinoxaline 1,4-dioxides represent a prospective scaffold for search of new compounds with improved chemotherapeutic characteristics. Novel 2-acyl-3-trifluoromethylquinoxaline 1,4-dioxides with alteration of substituents at position 2 and 6 were synthesized via nucleophilic substitution with piperazine moiety and evaluated against a broad panel of bacteria and fungi by measuring their minimal inhibitory concentrations. Their mode of action was assessed by whole-genomic sequencing of spontaneous drug-resistant Mycobacterium smegmatis mutants, followed by comparative genomic analysis, and on an original pDualrep2 system. Most of the 2-acyl-3-trifluoromethylquinoxaline 1,4-dioxides showed high antibacterial properties against Gram-positive strains, including mycobacteria, and the introduction of a halogen atom in the position 6 of the quinoxaline ring further increased their activity, with 13c being the most active compound. The mode of action studies confirmed the DNA-damaging nature of the obtained quinoxaline 1,4-dioxides, while drug-resistance may be provided by mutations in redox homeostasis genes, encoding enzymes potentially involved in the activation of the compounds. This study extends views about the antimicrobial and antifungal activities of the quinoxaline 1,4-dioxides and can potentially lead to the discovery of new antibacterial drugs.

KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge

KRAS mutation occurs in nearly 30% of human cancers, yet the most prevalent and oncogenic KRAS(G12D) variant still lacks inhibitors. Herein, we designed a series of potent inhibitors that can form a salt bridge with KRAS’s Asp12 residue. Our ITC results show that these inhibitors have similar binding affinity with both GDP-bound and GTP-bound KRAS(G12D), and our crystallographic studies reveal the structural basis of inhibitor binding-induced switch-II pocket in KRAS(G12D), experimentally confirming the formation of a salt bridge between the piperazine moiety of the inhibitors and the Asp12 residue of the mutant protein. Among KRAS family proteins and mutants, both ITC and enzymatic assays demonstrate the selectivity of the inhibitors for KRAS(G12D); and the inhibitors disrupt the KRAS–CRAF interaction. We also observed the inhibition of cancer cell proliferation as well as MAPK signaling by a representative inhibitor (TH-Z835). However, since the inhibition was not fully dependent on KRAS mutation status, it is possible that our inhibitors may have off-target effects via targeting non-KRAS small GTPases. Experiments with mouse xenograft models of pancreatic cancer showed that TH-Z835 significantly reduced tumor volume and synergized with an anti-PD-1 antibody. Collectively, our study demonstrates proof-of-concept for a strategy based on salt-bridge and induced-fit pocket formation for KRAS(G12D) targeting, which warrants future medicinal chemistry efforts for optimal efficacy and minimized off-target effects.

A two-stage degradation coupling photocatalysis to microalgae enhances the mineralization of enrofloxacin

The coupling of photocatalytic and algal processes has been used for the removal of widespread antibiotics. The removal capacities of the individual and the combined system against enrofloxacin were tested and compared in this work. Due to the low tolerance of the algae to enrofloxacin, the target compound was barely degraded during the individual algal treatment. In the individual photocatalytic process, the mineralization efficiency (defined as the ratio between the produced carbon dioxide and the initial) reached ∼57% with the remaining formed as transformation products. In contrast, a two-stage treatment incorporating photocatalytic and algal processes removed enrofloxacin completely and increased the mineralization efficiency to ∼64% or more. The addition of the citric acid as external co-substrate further elevated the mineralization efficiency with a factor of 1.25 compared to that of the individual photocatalysis. Different degradation products in both individual and integrated processes were identified and compared. The degradation pathways were found to involve the attack of the piperazine moiety and quinolone core. The results indicated the potential application of the combined photocatalytic-algal treatment in removal of veterinary antibiotics and improved our understanding of the underlying mechanisms and pathways.

The 4-(dimethylaminoalkyl)piperazine inhibitors of α-glucosidase: allosteric enzyme inhibition and identification of interacting chemical groups.

In continuation of our interest in identifying new α-glucosidase inhibitors with potential to become antidiabetic drugs, this work focuses on the study of 4-(dimethylaminoalkyl)piperazine-1-carbodithioate derivatives as α-glucosidase inhibitors. The eight heterocyclic piperazine-dithiocarbamate complexes studied in this work contain a variety of substitutions on their benzene ring exhibiting potent, noncompetitive inhibition of α-glucosidase. Dithiocarbamate and piperazine moieties are important pharmacophores with promising therapeutic prospects featuring facilitated drug delivery due to their lipophilic nature in addition to their α-glucosidase inhibitory activity. Enzyme kinetics, molecular dynamics simulations, and docking studies revealed that the target compounds bind to a new allosteric site that is located near the active site of α-glucosidase. Majority of molecular interactions of the compounds with the enzyme are mediated by hydrophobic contacts in addition to a number of important polar interactions. The current work identifies a number of chemical groups in the compounds that are responsible for potent inhibition of α-glucosidase. Moreover, it also provides new insights into understanding α-glucosidase inhibition by dithiocarbamate and piperazine-containing compounds that can be promising for development of new antidiabetic drugs.

Solvent-polarity reconfigurable fluorescent 4-piperazino-N-aryl-1,8-naphthalimide crown ether logic gates.

Four compounds 1-4 were designed and synthesised, comprising a 4-amino-N-aryl-1,8-naphthalimide fluorophore, a piperazine receptor, and an aryl group, as fluorescent logic gates. At the imide position, the substituent is phenyl (1), 1,2-dimethoxyphenyl (2), benzo-15-crown-5 (3), or benzo-18-crown-6 (4). Molecules 1 and 2 are constructed according to a fluorophore-spacer-receptor format, while 3 and 4 are engineered according to a receptor1-spacer1-fluorophore-spacer2-receptor2 format based on photoinduced electron transfer and internal charge transfer mechanisms. The compounds were studied in water, water/methanol mixtures of different ratios, and methanol by UV-visible absorption and steady-state fluorescence spectroscopy, as a function of pH, metal ions and solvent polarity. The excited state of 1-4 is 8.4 ± 0.2 in water, 7.6 ± 0.1 in 1 : 1 (v/v) water/methanol, and 7.1 ± 0.3 in methanol. The of 3 in water is 0.92 and the and of 4 in water are 2.3 and 2.9. 1H NMR data in D2O and CD3OD confirm H+ interaction at the piperazine moiety, and Na+ and Ba2+ binding at the benzo-15-crown-5 and benzo-18-crown-6 moieties of 3 and 4. By altering the solvent polarity, the fluorescent logic gates can be reconfigured between TRANSFER logic and AND logic. Molecules with polarity reconfigurable logic could be useful tools for probing the microenvironment of cellular membranes and protein interfaces.

Novel imidazo[1,2-a]pyridine derivatives as potent ATX allosteric inhibitors: Design, synthesis and promising in vivo anti-fibrotic efficacy in mice lung model

Aiming to develop novel allosteric autotaxin (ATX) inhibitors, hybrid strategy was utilized by assembling the benzyl carbamate fragment in PF-8380 onto the imidazo[1,2-a]pyridine skeleton of GLPG-1690. The piperazine moiety in GLPG-1690 was replaced with phenyl ring to enhance the π-π interactions with adjacent residues. In the light of FS-3 based ATX enzymatic assay, further structure-guided optimizations were implemented by exploring the substituents within the carbamate aromatic moiety and examining the effect of the 2-ethyl. Eventually, 13c bearing 1,3-benzodioxole and 2-hydroxyethyl piperazine group was identified as a powerful ATX inhibitor with an IC50 value of 2.7 nM. Subsequently, 13c was forwarded into an in vivo bleomycin-induced mice lung fibrosis model. In histopathological and immunohistochemical assays, 13c could typically alleviate the severity of fibrosis tissues and effectively reduce the deposition of fibrotic biomarker α-SMA. At a dose of 60 mg/kg, 13c was observed equivalent or even better potency than GLPG-1690 with a significant inhibition of the in vivo ATX activity. Except for the fundamental H-bond and π-π interactions, an extra H-bond between the 1,3-benzodioxole (O atom) and Phe306 offered great rationale in constraining the binding conformation of 13c. Finally, binding free energy calculation was conducted to assist in the efficient identification of allosteric ATX inhibitors.

New 15-membered macrocyclic Schiff base ligand; synthesis some Cd(II), Mn(II) and Zn(II) complexes, crystal structure, cytotoxicity, antibacterial and antioxidant activity

Herein, we aim at preparing 15-membered-ring symmetrical pentaaza macrocyclic Schiff base complexes using a template approach, based on the condensation reaction of an amine containing piperazine moiety, 2,2-(piperazine1,4-diyl)dianiline, and 2,6-diacetylpyridine in 1:1 mol ratio while Cd(II), Mn(II) and Zn(II) metal ions are present. Moreover, FT-IR, mass spectrometry, magnetic susceptibility measurements, UV–Vis and, 1H and 13C NMR spectroscopy were used to characterize these Schiff base complexes. Besides, the structure of [C25H25N5CdBr][ClO4] was determined using a single crystal X-ray structural analysis. Being in a pentagonal planar coordination environment, the Cd atom is surrounded by a Br atom in the apical position and 5 nitrogen atoms in the pentagonal plane. We also aimed at screening the synthesized complexes to investigate their antioxidant activities applying the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical scavenging assay. also, their bactericidal activity was evaluated using a paper disk diffusion method against both Gram-negative and Gram-positive bacteria, revealing a strong antioxidant activity and moderate effectiveness against all the tested bacteria. Finally, it is worth mentioning that the complex cytotoxicity was evaluated against MCF-7 (breast) and A549 (lung) adenocarcinoma cells. Generally, as compared to [ZnLBr]ClO4 possessed a greater cytotoxic effect against the tested cells.

Pyrimidine-Piperazine Hybrids; Recent Synthesis and Biological Activities

Pyrimidine and piperazine are well known as being the backbone of many bulky compounds and a vital core structure in approved drugs; previous studies have shown that combining a pyridine ring with a piperazine moiety within a single structural framework enhances biological activity. Despite vast resources enriched with a heterocyclic hybrid structure, a few reported studied on the synthesis and biological activities of pyrimidine-piperazine analogs were discussed. In this review, we summarize current design methods for the construction of pyrimidine-piperazine hybrids by coupling substituted piperazine on various positions of a pyrimidine ring and studied their biological studies.

Histamine H3 receptor antagonists with peptidomimetic (keto)piperazine structures to inhibit Aβ oligomerisation

Alzheimeŕs disease (AD) is the most prominent neurodegenerative disorder with high medical need. Protein-protein-interactions (PPI) interactions have a critical role in AD where β-amyloid structures (Aβ) build toxic oligomers. Design of disease modifying multi target directed ligand (MTDL) has been performed, which disable PPI on the one hand and on the other hand, act as procognitive antagonists at the histamine H3 receptor (H3R). The synthetized compounds are structurally based on peptidomimetic amino acid-like structures mainly as keto, diketo-, or acyl variations of a piperazine moiety connected to an H3R pharmacophore. Most of them showed low nanomolar affinities at H3R and some with promising affinity to Aβ-monomers. The structure–activity relationships (SAR) described offer new possibilities for MTDL with an optimized profile combining symptomatic and potential causal therapeutic approaches in AD.

Piperazine squaric acid diamides, a novel class of allosteric P2X7 receptor antagonists

The P2X7 receptor (P2X7R) stands out among the purinergic receptors due to its strong involvement in the regulation of tumor growth and metastasis formation as well as in innate immune responses and afferent signal transmission. Numerous studies have pointed out the beneficial effects of P2X7R antagonism for the treatment of a variety of cancer types, inflammatory diseases, and chronic pain. Herein we describe the development of novel P2X7R antagonists, incorporating piperazine squaric diamides as a central element. Besides improving the antagonists’ potency from pIC50 values of 5.7–7.6, ADME properties (logD7.4 value, plasma protein binding, in vitro metabolic stability) of the generated compounds were investigated and optimized to provide novel P2X7R antagonists with drug-like properties. Furthermore, docking studies revealed the antagonists binding to the allosteric binding pocket in two distinct binding poses, depending on the substitution of the central piperazine moiety.

Distance Effects of Phenylpiperazine-Containing Methacrylic Polymers on Optical and Structural Properties.

New materials based on methacrylic polymers modified with 1-(4-nitrophenyl)piperazine side chains, differing in the distance of the chromophore from the polymer main chain and/or the separation between the chromophoric units in the chain, are obtained and characterized in terms of their potential applications in optoelectronic devices. The surface, structural, and optical properties of the investigated materials are determined using atomic force microscopy, spectroscopic ellipsometry combined with transmission measurements, Raman and Fourier transform infrared spectroscopy, as well as cyclic voltammetry. The relevant model systems are additionally analyzed with quantum chemical density functional theory calculations in order to enable the generalization of the structure–photophysical property relationships for the optimization of the material features. It is found that the structural modification of the material, relying on the transit of the piperazine moiety away from the main polymer chain, leads to the hypsochromic shift of the absorption spectrum. Moreover, the lowest refractive index values are obtained for the polymer with a distant ethylene group in the side-chains and increased separation between the piperazine units. It was shown that the optical energy band gaps of the investigated piperazine-containing polymers are in the range from 2.73 to 2.81 eV, which reveals their promising potential for the advances in photovoltaics, field effect transistors, or electrochromic devices as an alternative for other widely applied polymer materials.

Synthesis, characterization, in vitro cytotoxicity activity, and molecular docking studies of mononuclear and binuclear Macroacyclic Schiff base complexes

A number of binuclear and mononuclear macroacyclic Schiff base complexes containing piperazine moieties were synthesized. The binuclear complexes (M2L1) characterized by elemental analysis, IR and, also Ni(II) complex by a X-ray single crystal structural analysis. In this case, X-ray showed that each nickel atom is in a mer-N3O3 octahedral coordination environment. Moreover, mononuclear macroacyclic Schiff base complexes (ML2 and ML3) were prepared based on the condensation reaction of an amine containing piperazine moiety and 2-hydroxy banzaldehyde or formyl pyridine in 1:2 mol ratio in the presence of Ni(II), Cu(II), and Co(II) ions. All of compounds were characterized by elemental analyses, FT-IR, mass spectrometry and ligands characterized by 1H and 13C NMR spectroscopy. The cytotoxicity of the complexes was evaluated against two different cancer cell lines including MCF-7 (breast) and A549 (lung) adenocarcinoma cells. In general, binuclear complexes, possesses a higher cytotoxic effect against the tested cells than the other complexes. In addition, the biological assessment of complexes have been examined via molecular docking. As an interesting results, the binuclear complexes have the highest inhibition effect against cytotoxic receptors.

Synthesis of Novel Bivalent Hydrazino-Thymohydroquinone Analogs Derived from Thymoquinone as Potential Antimicrobial Agents

In our previous work, it was reported that thymoquinone (TQ) and some thymohydroquinone (THQ) derivatives were used as precursors for the synthesis of potential anticancer agents. Hence, as a part of our ongoing program in the design of biologically active compounds derived from TQ scaffold we herein investigated the synthesis of homo- and heteronuclear thymol dimers tethered through various linkers such as ethylene, butylene, acetyl and N,N’-acetyl piperazine groups. The newly prepared compounds were examined as antimicrobial agents. Compounds 7 and 8 bearing a piperazine moiety exhibited highest antibacterial activity comparing to TQ, THQ and ampicillin especially against Staphylococcus aureus bacteria with MIC value of 16 µg/mL. All compounds showed moderate antifungal activity against Candida albicans and Aspergillus fumigatus. Together, the new TQ-based bivalent lead might be serving as a promising scaffold for development of novel and potent antimicrobial agents.

A unique sequential C-S or N-S inductive cleavage and retro-Diels-Alder fragmentation mechanism for alkylsulfonyl piperidine- and piperazine-containing compounds.

BI 605906 undergoes a collision-induced dissociation (CID) fragmentation resulting in the loss of methylsulfinic acid and butadiene to produce a corresponding imine. The fragmentation is hypothesized to occur via inductive cleavage of the C-S bond, generating a six-membered cyclic ene, followed by the retro-Diels-Alder (RDA) reaction. The aim of this study was to provide mechanistic evidence for the proposed fragmentation by investigating the CID spectra of BI 605906 and other alkylsulfonyl piperidine- and piperazine-containing compounds. The positive electrospray ionization tandem mass spectrometric (ESI+ -MS/MS) fragmentations of BI 605906, D9 -BI 605906, GK02935, GK02942, ketoconazole, terazosin, and homopiperazine were investigated. Additionally, incubations of BI 605906 and GK02942 in human liver microsomes (HLM) preparations were conducted. Metabolite identification experiments were performed following these incubations to investigate corresponding in vitro metabolism. BI 605906, D9 -BI 605906, GK02935, and GK02942 demonstrated the same fragmentation pattern by generating a respective imine ion, supporting the hypothesized inductive cleavage and subsequent RDA mechanism. Ketoconazole and terazosin, which contain either an N-acetyl or tetrahydrofuranyl piperazine group, respectively, did not demonstrate this mechanism, notably because they do not have the alkylsulfonyl moiety as a good leaving group. Although homopiperazine contains an arylsulfonyl diazepane group, and the initial step produced an unsaturated diazepane ring, the subsequent RDA reaction was unable to proceed due to the absence of a six-membered cyclic ene intermediate. Additionally, we identified oxidative metabolites of BI 605906 and GK02942 in HLM incubations utilizing the proposed fragmentation pattern. In the mass spectrometer, compounds containing alkylsulfonyl piperidine or piperazine groups can undergo inductive cleavage, leading to a six-membered cyclic ene intermediate. This intermediate will then form a corresponding imine ion via the RDA reaction. A practical application of this work is to utilize this fragmentation for elucidating structures of metabolites arising from parent compounds containing alkylsulfonyl piperidine or piperazine moieties.

Enrofloxacin degradation in a heterogeneous electro-Fenton system using a tri-metal-carbon nanofibers composite cathode

In this study, enrofloxacin (ENR) degradation by heterogeneous electro-Fenton (hetero-EF) system using Fe/Co/Zn-tri-metal co-doped carbon nanofibers (Fe/Co/Zn@C-NCNFs-800) modified cathode, which was fabricated by simply carbonization of the electrospun Fe-Co-Zn-ZIF@PAN. It was observed that the Fe/Co/Zn@C-NCNFs-800 electrode showed rougher surface, better crystal shape, more graphitic structures, larger specific surface area (108.0131 m2 g−1) and pore volume (0.1109 cm3 g−1) after calcination. Further electrochemical analysis revealed that the calcinated electrode possessed greater catalytic activity towards two-electron oxygen reduction reactions (2e-ORR), smaller electrochemical impedance, and higher corrosion potential compared to the initial Fe-Co-Zn-ZIF@PAN precursor. Under an optimized condition (e.g., pH = 3, and current = 40 mA), this hetero-EF system achieved an extraordinary ENR degradation efficiency of 99.08% within 30 min and a TOC removal efficiency of 47.13% within 150 min. Meanwhile, a remarkable yield and generation rate of H2O2 (129.029 mg L−1 and 0.8602 mg L−1 min−1) and ·OH (36.388 mg L−1 and 0.2426 mg L−1 min−1) were obtained. ENR degradation process involved the electron transfer between ≡FeII/III and ≡CoII/III redox couples as well as capture electron directly from cathode, which reduced the consumption of H2O2 and promoted the utilization of H2O2. Radical scavenging and electron paramagnetic resonance (EPR) tests verified that 1O2 and HO2·/O2·- served as the dominant reactive oxygen species (ROS) for ENR degradation. The possible ENR degradation pathway was deduced to be the open rings of piperazine and quinolone moiety as well as transformation into ciprofloxacin (CIP) according to the identification of produced intermediates. The relatively low energy consumption (3.07 kWh·m−3 and 2.54 kWh·m−3·order−1) and low intermediates toxicity made the practical applications of this hetero-EF system a real possibility.

Dithiocarbamate derivatives inhibit α-glucosidase through an apparent allosteric site on the enzyme.

Dithiocarbamate derivatives possess diverse biological activities. This work further expands their activity profile by identifying seven benzylamine-containing dithiocarbamate derivatives with piperazine and piperidine substitutions at the main moiety, and five piperazine-containing dithiocarbamates with various substitutions at the piperazine moiety as new inhibitors of α-glucosidase. Compounds bearing the benzylamine moiety exhibited more potent inhibition of the enzyme than the piperazine derivatives. Majority of the compounds non-competitively inhibited α-glucosidase that led to the identification of a new allosteric site on the enzyme with the help of molecular dynamics and docking studies. These studies suggest that the compounds regulate inhibition of the enzyme by binding to an allosteric site that is located in the vicinity of the active site. This is the first report on the allosteric inhibition of α-glucosidase by dithiocarbamate derivatives that provides insights into the mechanism of inhibition of the enzyme at molecular level. Moreover, it also explores new avenues for drug development of α-glucosidase inhibitors as antidiabetic drugs.

Insight into photocatalytic degradation of ciprofloxacin over CeO2/ZnO nanocomposites: Unravelling the synergy between the metal oxides and analysis of reaction pathways

The aim of this study was to provide deep insight into photocatalytic degradation of ciprofloxacin (CIP) over CeO2/ZnO nanocomposites. Catalysts used in this work were synthesized by a simple co-precipitation method and fully characterized by means of XRD, nitrogen physisorption, TEM, UV–vis, PL and XPS. Degradation of CIP was tracked by UV–vis and LC-MS techniques and the mineralization efficiency was determined by TOC analyses. It was documented that CeO2/ZnO nanocomposites were ca. twice more active than undoped ZnO and ca. 10 times more active than pristine CeO2. The improved activity of the nanocomposites resulted from the formation of a Z-scheme heterojunction in which photo-excited electrons from the conduction band of ZnO migrate to the valence band of CeO2. Photocatalytic degradation of CIP over the nanocomposites was found to be a surface reaction in which CIP molecules adsorbed onto ZnO are directly oxidized by photogenerated holes (h+). Degradation of the antibiotic proceeded through two parallel pathways: i) pathway I (dominant) in which piperazine moiety of CIP molecules was selectively oxidized by h+, and ii) pathway II in which both fluoroquinolone and piperazine moieties of the antibiotic were degraded. The latter pathway required participation of both h+ and hydroxyl radicals (HO•).