Anti-Proliferative and Pro-Apoptotic Activities of Synthesized 3,4,5 Tri-Methoxy Ciprofloxacin Chalcone Hybrid, through p53 Up-Regulation in HepG2 and MCF7 Cell Lines.

BACKGROUND: Cancer is a significant health problem around the world and one of the leading causes of human death. The need for novel, selective and non-toxic anti-cancer agents is still urging. AIM OF THE WORK: to investigate the anti-proliferative and pro-apoptotic effects of the synthesized ciprofloxacin 3,4,5 tri-methoxy chalcone hybrid (CCH) on the HepG2 hepatocellular carcinoma and MCF7 breast carcinoma cell lines. MATERIALS AND METHODS: HepG2 and MCF7cell lines were treated with CCH. Cell viability and cell cycle analysis were performed. Protein and mRNA expression levels of P53, COX-2 and TNF-α were analyzed by western blotting and RT-PCR respectively. RESULTS: CCH caused concentration and time-dependent reduction in the viability of human HepG2 and MCF7 cells, pre-G1 apoptosis and cell cycle arrest at G2/M stage, significantly higher P53 and TNF-α mRNA and protein expression levels but significantly lower COX2 mRNA and protein expression levels. CONCLUSION: CCH showed obvious anti-proliferative and apoptosis-inducing activities in both cell lines.

In-vitro cytotoxic evaluation of newly designed ciprofloxacin-oxadiazole hybrids against human liver tumor cell line (Huh7).

Fluoroquinolones are targets of interest due to their broad spectrum antibacterial activity. Structure-activity relationship (SAR) of fluoroquinolones clearly indicates that substitution at C-7 position enhances the lipophilicity of these scaffolds resultantly affording pharmacologically significant compounds. Therefore, various ciprofloxacin-oxadiazole hybrids were synthesized and characterized by spectral analysis. Cytotoxic activity of these derivatives was assessed using human liver tumor cells (Huh7). One dose anticancer test results revealed moderate cytotoxicity of the newly synthesized compounds against this cell line. As the only compound 4a depicted comparatively lower cell viability value (81.91% using 100µg/mL concentration) than the other compounds.

Nitric Oxide Photo-Donor Hybrids of Ciprofloxacin and Norfloxacin: A Shift in Activity from Antimicrobial to Anticancer Agents.

The potential anticancer effect of fluoroquinolone antibiotics has been recently unveiled and related to their ability to interfere with DNA topoisomerase II. We herein envisioned the design and synthesis of novel Ciprofloxacin and Norfloxacin nitric oxide (NO) photo-donor hybrids to explore the potential synergistic antitumor effect exerted by the fluoroquinolone scaffold and NO eventually produced upon light irradiation. Anticancer activity, evaluated on a panel of tumor cell lines, showed encouraging results with IC50 values in the low micromolar range. Some compounds displayed intense antiproliferative activity on triple-negative and doxorubicin-resistant breast cancer cell lines, paving the way for their potential use to treat aggressive, refractory and multidrug-resistant breast cancer. No significant additive effect was observed on PC3 and DU145 cells following NO release. Conversely, antimicrobial photodynamic experiments on both Gram-negative and Gram-positive microorganisms displayed a significant killing rate in Staphylococcus aureus, accounting for their potential effectiveness as selective antimicrobial photosensitizers.

Impact of Critical Material Attributes (CMAs)-Particle Shape on Miniature Pharmaceutical Unit Operations.

The U.S. Food and Drug Administration (FDA) emphasizes drug product development by Quality by Design (QbD). Critical material attributes (CMAs) are a QbD element that has an impact on pharmaceutical operations and product quality. Pharmaceutical drugs often crystallize as needle-shaped (a CMA) particles and affect the process due to poor flowability, low bulk density, and high compressibility, and eventually the product performance. In this study, the product obtained from crystallization was needle-shaped Ciprofloxacin HCl (CIPRO), formed lumps during drying, and compacted during processing through feeders. To delump small amounts of materials and break the needles, multiple available devices (mortar-pestle, Krups grinder) and custom-made grinder were assessed before formulation. The processed CIPRO powder was then used to make tablets in the miniature tablet manufacturing unit developed by the team at MIT. The critical quality attributes (CQA) of the tablets, set by the United States Pharmacopeia (USP), were then assessed for the drug powder processed with each of these devices. Powder properties comparable to commercial CIPRO were obtained when the custom MIT-designed grinder was used, leading to tablets that meet the USP criteria, with comparable dissolution profiles of those for marketed CIPRO tablets. This study demonstrates how needle-shaped crystals have an impact on pharmaceutical operations, even if it is on a miniature scale, and how proper shape and subsequent flow properties can be obtained by processing the particles through the MIT team-designed grinder.

3,7-bis-benzylidene hydrazide ciprofloxacin derivatives as promising antiproliferative dual TOP I & TOP II isomerases inhibitors.

We report herein design and synthesis of a new series of 3,7-bis-benzylidenes of ciprofloxacin. Most of the target compounds revealed good cytotoxic activity; the most potent 4e and 4i achieved strong broad spectrum antiproliferative activity with comparable activity to Doxorubicin with IC50 (µM) of 1.21 ± 0.02, 0.87 ± 0.04, 1.21 ± 0.02; 0.41 ± 0.02, 0.57 ± 0.06, 1.31 ± 0.04 and 1.26 ± 0.01, 1.79 ± 0.04, 0.63 ± 0.01 against leukemia cancer cell line HL-60 (TB), colon cancer cell line HCT-116 and breast cancer cell line MCF7, respectively. Moreover, the most potent derivative 4i induced apoptosis at G2/M phase Investigating the mechanism of action of compounds 4e, 4 h and 4i exhibited promising dual TOP Iα and TOP IIB % inhibition comparable to Camptothecin and Etoposide; respectively. Docking of 4e, 4 h and 4i into the active site of topo I and II proteins compared to Camptothein and Etoposide revealed acceptable binding score and augmented enzyme assay data. Hence, 4e and 4i are promising targeted antiproliferative dual acting TOP Iα TOP IIB inhibitors that require further optimization.

Antibiotic resistance and drug modification: Synthesis, characterization and bioactivity of newly modified potent ciprofloxacin derivatives.

Development of new derivatives of commercial antibiotics using different organic reagents and testing these derivatives against different microorganisms are the main goals of this article. Thus, the antibiotic ciprofloxacin, CF, was acylated via reaction with ethyl cyanoacetate and ethyl acetoacetate in basic medium to give the cyanoacetylpiprazinyl dihydroquinoline derivative 3, and oxobutanoylpiprazinyl dihydroquinoline derivative 5, respectively. On the other hand, N-alkylated derivatives 8-10, were prepared through the reaction of CF with chloroacetonitrile, chloroacetyl acetone and chloroacetone in the presence of carbonate salt. In basic medium, both 3 and 10 were coupled with benzenediazonium chloride to afford hydrazono derivatives, which were then cyclized to give 4-(dihydropyridazinecarbonyl)piperazinyl-1,4-dihydroquinoline. Furthermore, compounds 3 and 10 were reacted with benylidenemalononitrile to produce 4H-pyan and pyrido[1,2-a]pyrazine derivatives, respectively. Both 3 and 10 were reacted with DMFDMA to give enaminone derivatives. These enaminones were cyclized to aminopyrimidine derivatives by reacting with urea or thiourea. X-ray, elemental analysis and spectral data were used to illustrate and confirm the structures of the isolated compounds. The bioactivities of the novel compounds were investigated against different gram-positive and gram-negative bacteria. In addition, these novel antibiotic derivatives were tested against ciprofloxacin-resistant bacteria isolated from patients aged 65-74 years. This study reveals that most of the modified drugs show high to moderate antibacterial activity. Additionally, these drugs show good effects against ciprofloxacin-resistant bacteria.

Novel urea linked ciprofloxacin-chalcone hybrids having antiproliferative topoisomerases I/II inhibitory activities and caspases-mediated apoptosis.

A novel series of urea-linked ciprofloxacin (CP)-chalcone hybrids 3a-j were synthesized and screened by NCI-60 cancer cell lines as potential cytotoxic agents. Interestingly, compounds 3c and 3j showed remarkable antiproliferative activities against both colon HCT-116 and leukemia SR cancer cells compared to camptothecin, topotecan and staurosporine with IC50 = 2.53, 2.01, 17.36, 12.23 and 3.1 µM for HCT-116 cells, respectively and IC50 = 0.73, 0.64, 3.32, 13.72 and 1.17 µM for leukemia SR cells, respectively. Also, compounds 3c and 3j exhibited inhibitory activities against Topoisomerase (Topo) I with % inhibition = 51.19% and 56.72%, respectively, compared to camptothecin (% inhibition = 60.05%) and Topo IIß with % inhibition = 60.81% and 60.06%, respectively, compared to topotecan (% inhibition = 71.09%). Furthermore, compound 3j arrested the cell cycle of leukemia SR cells at G2/M phase. It induced apoptosis both intrinsically and extrinsically via activation of proteolytic caspases cascade (caspases-3, -8, and -9), release of cytochrome C from mitochondria, upregulation of proapoptotic Bax and down-regulation of Bcl-2 protein level. Thus, the new ciprofloxacin derivative 3j could be considered as a potential lead for further optimization of antitumor agent against leukemia and colorectal carcinoma.

Design, Synthesis and Pharmacological Evaluation of Some C3 Heterocyclic-Substituted Ciprofloxacin Derivatives as Chimeric Antitubercular Agents.

A series of new C3 heterocyclic-substituted ciprofloxacin derivatives were prepared from ciprofloxacin acid hydrazide as possible chimeric molecules. They were evaluated for their possible in vitro antibacterial (agar cup/bore diffusion method) and antitubercular (Lowenstein-Jensen (LJ) slant method) activities. The results indicated that all the test compounds are highly effective against all the bacterial strains and have shown excellent anti-tubercular activity against normal, multidrug resistant and extensively drug resistant strains of Mycobacterium tuberculosis. They were found to be more potent antibacterial and antitubercular agents than the standard, ciprofloxacin. The minimum inhibitory concentration (MIC)'s of all the compounds against M. tuberculosis were found to be 0.0625 µg/mL as compared to ciprofloxacin (MIC = 2 to > 8 µg/mL). Molecular docking studies were performed by using AUTODOCK 4.2 on the new ciprofloxacin derivatives at the active site of crystal structure of fluoroquinolones target enzyme Mtb DNA gyrase GyrA N-terminal domain (PDB ID: 3ILW) and also on the active site of crystal structure of chosen heterocyclics target enzyme enoyl-acyl carrier protein (ACP) reductase enzyme (PDB ID: 4TZK). Interestingly, almost all the compounds have shown relatively greater binding affinity at both the active sites than ciprofloxacin. Compound 6 exhibited the highest affinity for 3ILW and 4TZK.

Synthesis and biological assessment of ciprofloxacin-derived 1,3,4-thiadiazoles as anticancer agents.

The quinolone-3-carboxylic acid scaffold is essential structure for antibacterial activity of fluoroquinolones such as ciprofloxacin. Modification of 3-carboxylic functionality in this structure can be used for switching its activity from antibacterial to anticancer. Accordingly, a series of C-3 modified ciprofloxacin derivatives containing N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-carboxamide moiety was synthesized as novel anticancer agents. Most of compounds showed significant activity against MCF-7, A549 and SKOV-3 cancer cells in the MTT assay. In particular, compounds 13a-e and 13g were found to be as potent as standard drug doxorubicin against MCF-7 cell line (IC50s = 3.26-3.90 µM). Furthermore, the 4-fluorobenzyl derivatives 13h and 14b with IC50 values of 3.58 and 2.79 µM exhibited the highest activity against SKOV-3 and A549 cells, being as potent as doxorubicin. Two promising compounds 13e and 13g were further tested for their apoptosis inducing activity and cell cycle arrest. Both compounds could significantly induce apoptosis in MCF-7 cells, while compound 13e was more potent apoptosis inducer resulting in an 18-fold increase in the proportion of apoptotic cells at the IC50 concentration in MCF-7 cells. The cell cycle analysis revealed that compounds 13e and 13g could increase cell portions in the sub-G1 phase, inducing oligonucleosomal DNA fragmentation and apoptosis confirmed by comet assay.

Synthesis, evaluation of thymidine phosphorylase and angiogenic inhibitory potential of ciprofloxacin analogues: Repositioning of ciprofloxacin from antibiotic to future anticancer drugs.

Over expression of thymidine phosphorylase (TP) in various human tumors compared to normal healthy tissue is associated with progression of cancer and proliferation. The 2-deoxy-d-ribose is the final product of thymidine phosphorylase (TP) catalyzed reaction. Both TP and 2-deoxy-d-ribose are known to promote unwanted angiogenesis in cancerous cells. Discovery of potent inhibitors of thymidine phosphorylase (TP) can offer appropriate approach in cancer treatment. A series of ciprofloxacin 2, 3a-3c, 4a-4d, 5a-5b, 6 and 7 has been synthesized and characterized using spectroscopic techniques. Afterwards, inhibitory potential of synthesized ciprofloxacin 2, 3a-3c, 4a-4d, 5a-5b, 6 and 7 against thymidine phosphorylase enzyme was assessed. Out of these twelve analogs of ciprofloxacin nine analogues 3a-3c, 4a-4c, 5a-5b and 6 showed good inhibitory activity against thymidine phosphorylase. Inhibitory activity as presented by their IC50 values was found in the range of 39.71 ± 1.13 to 161.89 ± 0.95 µM. The 7-deazaxanthine was used as a standard inhibitor with IC50 = 37.82 ± 0.93 µM. Furthermore, the chick chorionic allantoic membrane (CAM) assay was used to investigate anti-angiogenic activity of the most active ciprofloxacin-based inhibitor 3b. To enlighten the important binding interactions of ciprofloxacin derivatives with target enzyme, the structure activity relationship and molecular docking studies of chosen ciprofloxacin analogues was discussed. Docking studies revealed key π-π stacking, π-cation and hydrogen bonding interactions of ciprofloxacin analogues with active site residues of thymidine phosphorylase enzyme.

Anticancer and antimicrobial effects of novel ciprofloxacin fatty acids conjugates.

Ciprofloxacin (CP) has a confirmed cytotoxic action on some cancerous cells, but in high, non-pharmacological concentrations. Considering features of natural fatty acids, such as biocompatibility, biodegradability and their increased cellular uptake by cancer cells, it seems that combining them with a drug could improve its bioavailability, and thus cytotoxicity. Therefore, the aim of this study was coupling of CP with saturated and unsaturated fatty acids, and evaluation of their cytotoxicity, apoptosis-inducing effects and inhibition of IL-6 release in human primary (SW480) and metastatic (SW620) colon cancer, metastatic prostate cancer (PC3) and normal (HaCaT) cell lines. The PC3 cell line was the most sensitive to the presence of the obtained conjugates. The value of IC50 for oleic acid conjugate (4) was 7.7 µM, and it was 12 times lower than for CP alone (101.4 µM). The studied derivatives induced late apoptosis in all cancer cell lines, but not in normal cells. The most potent apoptosis inducer was conjugate 4, that resulted in the highest percentage of PC3 cells in late apoptosis (81.5% ±â€¯3.9), followed by elaidic acid amide 5 (75% ±â€¯4.8). The strongest pro-apoptic effects on SW480 cells were demonstrated by conjugates of DHA (8) and sorbic (2) acids, whereas in SW620 cell lines, compounds 2 and 5 appeared to be the most effective. To establish the mechanism of cytotoxic action of derivatives 2, 4, 5, the level of interleukin-6 (IL-6) was measured. The compounds with the highest cytotoxic potential significantly decreased the release of IL-6 by cancer cells. Additionally, all conjugates were evaluated for their in vitro antimicrobial activity. Short chain amides - crotonic (1) and sorbic (2) - were the most active against Staphyloccoci. The second-mentioned amide has shown both strong antistaphylococcal and antitumor properties.

Design, synthesis, and evaluation of compounds capable of reducing Pseudomonas aeruginosa virulence.

Anti-virulence approaches in the treatment of Pseudomonas aeruginosa (PA)-induced infections have shown clinical potential in multiple in vitro and in vivo studies. However, development of these compounds is limited by several factors, including the lack of molecules capable of penetrating the membrane of gram-negative organisms. Here, we report the identification of novel structurally diverse compounds that inhibit PqsR and LasR-based signaling and diminish virulence factor production and biofilm growth in two clinically relevant strains of P. aeruginosa. It is the first report where potential anti-virulent agents were evaluated for inhibition of several virulence factors of PA. Finally, co-treatment with these inhibitors significantly reduced the production of virulence factors induced by the presence of sub-inhibitory levels of ciprofloxacin. Further, we have analyzed the drug-likeness profile of designed compounds using quantitative estimates of drug-likeness (QED) and confirmed their potential as hit molecules for further development.

Antibiotic-Based Conjugates Containing Antimicrobial HLopt2 Peptide: Design, Synthesis, Antimicrobial and Cytotoxic Activities.

Recent studies have shown that modified human lactoferrin 20-31 fragment, named HLopt2, possesses antibacterial and antifungal activity. Thus, we decided to synthesize and evaluate the biological activity of a series of conjugates based on this peptide and one of the antimicrobials with proven antibacterial (ciprofloxacin, CIP, and levofloxacin, LVX) or antifungal (fluconazole, FLC) activity. The drugs were covalently connected to the peptide via amide, methylenecarbonyl moieties, or a disulfide bridge. The antibacterial and antifungal activities were evaluated under Clinical and Laboratory Standard Institute (CLSI) recommended conditions or in a low-salt brain-heart infusion diluted medium (BHI1/100). Results showed that conjugation of the peptide with the drug increased its antimicrobial activity up to 4-fold. Under CLSI-recommended conditions, all the compounds revealed rather low efficiency. Among conjugates, the highest antibacterial activity was recorded for the CIP-Cys-S-S-HLopt2-NH2 (III). In BHI1/100, which had lower differentiating properties, all of the conjugates revealed low MIC and MMC (minimum inhibitory and microbicidal concentrations) values. The disulfide bridge used as a linker in the most active conjugate (III) upon incubation with S. aureus cells is reduced, releasing constituent peptide and CIP-Cys. In addition, we showed that its fluorescently labeled analogue and constituent peptide are able to be internalized into both C. albicans and S. aureus cells. Moreover, the invaluable advantage of the presented conjugates was their low toxicity to mammalian cells and very low hemolytic activity. The current research can form a solid basis for further in vivo studies and drug development.

Design, synthesis, and antimycobacterial activity of novel ciprofloxacin derivatives.

Tuberculosis is the deadliest infectious disease affecting humankind with a death toll of approximately 1.7 million people in 2016. The increasing prevalence of multidrug-resistant strains of the causative pathogen, Mycobacterium tuberculosis (Mtb) which results in reduced effectiveness of the current therapies, underscores the urgent need for the development of new antitubercular drugs. In the search for such drugs, we investigated two series of ciprofloxacin (CPX) derivatives (analogues and hybrids). We herein report the design, synthesis, and biological activity of these series against the human virulent Mtb H37Rv strain in vitro. The small propionyl analogue 11 (MIC90 1.6 µM; SI > 61) and the large cholesteryl hybrid 32 (MIC90 2.0 µM; SI > 6) were the most active derivatives, comparable to CPX (MIC90 1.8 µM). However, the slightly less active but non-cytotoxic para-fluorobenzyl hybrid 28 (MIC90 3.7 µM; SI 27) was more selective toward bacteria than 32. Thus, the CPX derivatives 11 and 28 were identified as preferred antitubercular hits for further investigation including distribution, metabolism and pharmacokinetic parameters determination and in vivo activity assessment in animal models.

A Consolidated and Continuous Synthesis of Ciprofloxacin from a Vinylogous Cyclopropyl Amide.

Ciprofloxacin is a broad-spectrum antibiotic that is recognized as one of the World Health Organization's Essential Medicines. It is particularly effective in the treatment of Gram-negative bacterial infections associated with urinary, respiratory, and gastrointestinal tract infections. A streamlined and high yielding continuous synthesis of ciprofloxacin has been developed, which employs a chemoselective C-acylation step that precludes the need for intermediate isolations, extractions, or purifications. The end-to-end process has a residence time of 4.7 min with a 15.8 g/h throughput at laboratory scale and an overall isolated yield of 83%.

Targeted Antibacterial Activity Guided by Bacteria-Specific Nitroreductase Catalytic Activation to Produce Ciprofloxacin.

Fluoroquinolones (FQs) are among the front-line antibiotics used to treat severe infections caused by Gram-negative bacteria. However, recently, due to toxicity concerns, their use has been severely restricted. Hence, efforts to direct delivery of this antibiotic specifically to bacteria/site of infection are underway. Here, we report a strategy that uses a bacterial enzyme for activation of a prodrug to generate the active antibiotic. The ciprofloxacin-latent fluorophore conjugate 1, which is designed as a substrate for nitroreductase (NTR), a bacterial enzyme, was synthesized. Upon activation by NTR, release of Ciprofloxacin (CIP) as well as a fluorescence reporter was observed. We provide evidence for the prodrug permeating bacteria to generate a fluorescent signal and we found no evidence for activation in mammalian cells supporting selectivity of activation within bacteria. As a testament to its efficacy, 1 was found to have potent bactericidal activity nearly identical to CIP and significantly reduced the bacterial burden in a neutropenic mouse thigh infection model, again, at comparable potency with CIP, a clinically used FQ. Thus, together, we have developed a small molecule that facilitates bacteria-specific fluoroquinolone delivery.

Encapsulation of ciprofloxacin within modified xanthan gum- chitosan based hydrogel for drug delivery.

The aim of the present work was to investigate the preparation of polyelectrolyte hydrogel as potential drug carrier for antibacterial Ciprofloxacin drug (CFX), intended for controlled release formulation. Hydrogel of N-trimehtyl chitosan (TMC)/sodium carboxymethyl xanthan gum (CMXG) was prepared and ciprofloxacin was employed as a model drug to investigate the loading and release performance of the prepared hydrogel. FTIR, DSC, TGA and SEM analysis were used to characterize the TMC/CMXG hydrogel and its CFX loaded hydrogel. The results showed that the ciprofloxacin was successfully incorporated and released from the prepared hydrogel without the loss of structural integrity or the change in its functionality. The encapsulation efficiency of CFX within the prepared hydrogel was found to be increased with increasing the concentration of drug reaching about 93.8 ±â€¯2.1% with concentration of CFX 250 µg/ml. It was shown also that the drug is entrapped within the gel without significant interaction as confirmed from FTIR spectra and DSC analysis. In vitro release study in phosphate buffer saline (PBS), indicated the steady rise in cumulative drug release with the highest release amount, reaching about 96.1 ±â€¯1.8% up to 150 min, whereby the gel with high drug loading efficiency (3.52 ±â€¯0.07%) displayed faster and higher release rate than that of gel containing a smaller amount of drug (0.44 ±â€¯0.01%). The release kinetics of loaded drug followed zero-order kinetics. CFX drug loaded hydrogel showed high activity against the gram positive and gram negative bacterial strains due to the successful released of CFX from the CFX loaded hydrogel into the tested bacterial strains with the highest diameter of inhibition zone against Escherichia coli (67.0 ±â€¯1.0) as compared to reference antibiotic, Gentamicin (28 ±â€¯0.5). Cytotoxicity of the prepared hydrogel was examined in vitro using lung human normal cell lines and showed the highest cell viability (97 ±â€¯0.5%) at concentration up to 50 µg/ml. Consequently, TMC/CMXG hydrogel can be proposed as new controlled release drug delivery system.

Proof-of-concept preparation and characterization of dual-drug amorphous nanoparticle complex as fixed-dose combination of poorly soluble drugs.

OBJECTIVES: To carry out a proof-of-concept study on the development of dual-drug amorphous nanoparticle complex (nanoplex in short) as a potential formulation platform for fixed-dose combination (FDC) of poorly-soluble drugs. SIGNIFICANCE: FDC has been proven effective in improving patient compliance for treatment that requires complex multidrug regimen. Currently, there is growing interest to develop FDC of poorly-soluble drugs due to the increased number of drugs exhibiting poor solubility thus low bioavailability. METHODS: The dual-drug nanoplex was prepared by electrostatically-driven co-complexation of drug molecules with oppositely charged dextran sulfate, using ciprofloxacin (CIP) and itraconazole (ITZ) as the model poorly-soluble drugs. RESULTS: We first verified that the co-complexation products were dual-drug CIP-ITZ nanoplex, and not binary mixtures of the single-drug CIP and ITZ nanoplexes, by demonstrating their distinct thermal behaviors and dissolution characteristics. Depending on the preparation condition, the dual-drug nanoplex exhibited size and zeta potential of 160-410 nm and -35-50 mV, respectively. The individual drug payloads were readily manipulated by varying the CIP/ITZ mass ratio in the feed, resulting in CIP and ITZ payloads in the range of 60-30% and 15-45%, respectively. The CIP-ITZ nanoplex, however, exhibited diminished CIP supersaturation generation, thus lower CIP solubility enhancement, compared to the single-drug CIP nanoplex. The CIP-ITZ nanoplex, nonetheless, remained capable of generating high ITZ supersaturation level. CONCLUSION: Dual-drug nanoplex was successfully prepared with a high degree of control over its physical characteristics. Nevertheless, whether dual-drug nanoplex always exhibits diminished solubility enhancement compared to its single-drug counterparts needs to be investigated using different poorly-soluble drugs.

Comparing a Statistical Model and Bayesian Approach to Establish the Design Space for the Coating of Ciprofloxacin HCl Beads at Different Scales of Production.

The primary objective of this study was to compare two methods for establishing a design space for critical process parameters that affect ethylcellulose film coating of multiparticulate beads and assess this design space validity across manufacturing scales. While there are many factors that can affect film coating, this study will focus on the effects processing conditions have on the quality and extent of film formation, as evaluated by their impact coating yield and drug release. Ciprofloxacin HCl layered beads were utilized as an active substrate core, ethylcellulose aqueous dispersion as a controlled release polymer, and triethyl citrate as a plasticizer. Thirty experiments were conducted using a central composite design to optimize the coating process and map the response surface to build a design space using either statistical least squares or a Bayesian approach. The response surface was fitted using a linear two-factor interaction model with spraying temperature, curing temperature, and curing time as significant model terms. The design spaces established by the two approaches were in close agreement with the statistical least squares approach being more conservative than the Bayesian approach. The design space established for the critical process parameters using small-scale batches was tested using scale-up batches and found to be scale-independent. The robustness of the design space was confirmed across scales and was successfully utilized to establish process signature for the coating process.

Synthesis, theoretical, spectroscopic and electrochemical DNA binding investigations of 1, 3, 4-thiadiazole derivatives of ibuprofen and ciprofloxacin: Cancer cell line studies.

Two new 1,3,4-thiadiazole derivatives of ibuprofen and ciprofloxacin namely {(5-(1-(4-isobutylphenyl)ethyl)-1,3,4-thiadiazol-2-amine)} 1 and {(3-(5-amino-1,3,4-thiadiazol-2-yl)-1-cyclopropyl-6-fluoro-7-(piperazin-1-yl)quinolin-4(1H)-one)} 2 were synthesized and characterized by spectroscopic and elemental analysis. DFT and molecular docking were done initially for theoretical binding possibilities of the investigated compounds. In vitro DNA binding investigations were carried out with UV-visible spectroscopic, fluorescence spectroscopic, cyclic voltammetric (CV) experiments under physiological conditions of the stomach (4.7) and blood (7.4) pH and at normal body temperature (37 °C). Both theoretical and experimental results suggested spontaneous and significant intercalative binding of the compounds with DNA. Kinetic and thermodynamic parameters (Kb, ΔG) were evaluated greater for compound 2 which showed comparatively more binding and more spontaneity of 2 than 1 to bind with DNA at both pH values. Binding site sizes were found greater (n > 1) and revealed the possibility of other sites for interactions along with intercalation. Overall results for DNA binding were found more significant for 2 at Stomach (4.7) pH. Viscometric studies further verified intercalation as a prominent binding mode for both compounds. IC50 values obtained from human hepatocellular carcinoma (Huh-7) cell line studies revealed 2 as potent anticancer agent than 1 as value found 25.75 µM (lesser than 50 µM). Theoretical and experimental DNA binding studies showed good correlation with cancer cell (Huh-7) line activity of 1 and 2 and further suggested that these compounds could act as potential anti-cancer drug candidates.