Naringenin-Zinc Oxide Nanocomposites Amalgamated Polymeric Gel Augmented Drug Delivery and Attenuated Experimental Cutaneous Candidiasis in Balb/c Mice: In Vitro and In Vivo Studies.

Naringenin (NRG) inhibits the fungal 17ß-hydroxysteroid dehydrogenase accountable for ergosterol synthesis in Candida albicans (C. albicans), a causative agent for cutaneous candidiasis. In present research, NRG was complexed with ZnO nanomaterial (NRG-Zn2+) to synthesize NRG-Zn2+ nanocomposites. The particle size and ζ-potential of NRG-Zn2+ nanocomposites were respectively estimated to be 180.33 ± 1.22-nm and - 3.92 ± 0.35-mV. In silico data predicted the greater affinity of NRG-Zn2+ nanocomposite for 14α-demethylase and ceramide in comparison to NRG alone. Later, NRG-Zn2+ nanocomposites solution was transformed in to naringenin-zinc oxide nanocomposites loaded chitosan gel (NRG-Zn-CS-Gel) with viscosity and firmness of 854806.7 ± 52386.43 cP and 698.27 ± 10.35 g, respectively. The ex-vivo skin permeation demonstrated 70.49 ± 5.22% skin retention, significantly greater (P < 0.05) than 44.48 ± 3.06% of naringenin loaded chitosan gel (NRG-CS-Gel) and 31.24 ± 3.28% of naringenin solution (NRG Solution). NRG-Zn-CS-Gel demonstrated 6.71 ± 0.84% permeation of NRG with a flux value of 0.046 ± 0.01-µg/cm2/h. The MIC50 of NRG-Zn-CS-Gel against C. albicans was estimated to be 0.156-µg/mL with FICI (fractional inhibitory concentration index) of 0.018 that consequently exhibited synergistic efficacy. Further, NRG-Zn-CS-Gel demonstrated superior antifungal efficacy in C. albicans induced cutaneous candidiasis infection in Balb/c mice. The fungal burden in NRG-Zn-CS-Gel treated group was 109 ± 25 CFU/mL, significantly lower (P < 0.05) than positive control (2260 ± 446 CFU/mL), naringenin loaded chitosan gel (NRG-CS-Gel; 928 ± 127 CFU/mL) and chitosan gel (CS-Gel; 2116 ± 186 CFU/mL) treated mice. Further, histopathology examination and cytokine profiling of TNF-α, IL-1ß and IL-10 revealed the healing of skin and inflammation associated with cutaneous candidiasis infection. In conclusion, NRG-Zn-CS-Gel may be a potential candidate for translating in to a clinical viable topical nanotherapeutic.

Mapping Advantages and Challenges in Analytical Development for Fixed Dose Combination Products, a Review.

Formulations containing more than one active ingredient are increasingly gaining popularity due to advantages with regard to patient convenience as well as reduced cost of production, packaging, and transportation. Such fixed-dose combinations (FDCs) demand for enhanced analytical methodologies and tools to efficiently achieve quality control of these complex products as compared to the conventional products containing only one active constituent. Highly efficient analytical methods can measure multiple constituents at once, improving their quality control. This review article discusses the challenges in the development of such methods due to the similarities or differences in the chemical identity of the participating drug molecules in an FDC. The latest developments in multiple analyte determination using various analytical techniques (HPLC, LC-MS, NMR, IR, powder XRD and DSC) are discussed, with a focus on special considerations in each case. The article discusses challenges with sample preparation of complex FDC products, and the use of Chemometrics and Quality by Design to develop efficient analytical methods. Lastly, an equation-based approach is proposed and demonstrated to arrive at a parameter referred to as "percentage efficiency gain" that would be useful in directly accessing the relevance and commercial benefits of a simultaneous method vis-a-vis separate methods for individual components.

Synthon Approach in Crystal Engineering to Modulate Physicochemical Properties in Organic Salts of Chlorpropamide.

The formulation of drug with improved bioavailability is always challenging and indispensable in the field of pharmaceutics. The control of intermolecular interactions via crystal engineering approach and solid-state molecular recognition results in the formation of active drug molecules with modulated pharmacological benefits. Therefore, with the aim to improve the solubility and dissolution rate of the drug chlorpropamide (CPA), the mechanochemical liquid-assisted grinding (LAG) of the drug with several pharmaceutically accepted excipients was performed. This contributed to the discovery of six novel solid phases, namely salts, salt cocrystals and salt cocrystal hydrate─the salt of CPA with 3, 4-diaminopyridine (DAP); salt and salt cocrystal (SC) polymorph (Z″=3) with 1, 4-diazabicyclo [2.2.2] octane (DABCO); a salt, SC polymorph (Z″=9), and a SC hydrate (Z″=9) with piperazine (PIP). The formation of these salts and salt cocrystals are mainly guided by the strong hydrogen bonds with tunable strength having high electrostatic contribution. This attractive interaction brings the donor and the acceptor atoms close to each other for a facile proton transfer. Furthermore, the conformational constraints on the drug molecules, provided by the excipients via strong and directional hydrogen bonds, are quite impressive as this leads to the identification and characterization of "new conformational isomers" for the CPA molecules. The new crystalline phases exhibit enhanced intrinsic dissolution rate in comparison to that of the pure drug, the magnitude being 7, 131, and 120 folds for CPADAP, CPADABCO_II, and CPAPIP_III, respectively. Furthermore, it is interesting to note that the order of solubility is enhanced by 2.7-, 3-, and 7-fold, respectively, for the abovementioned salts. This also mirrors the trends in the magnitude of the binding energy, the higher magnitude being reflected in the lower solubility. Additionally, the in vivo experiments performed in SD rats results in the enhancement of the magnitude of the pharmacokinetic properties, when compared to the pristine drug. The concentration of the drug in CPADABCO_II and CPAPIP_III formulations exhibits 6- and 4-fold increments, respectively. Indeed, these results corroborate to the trends observed in the structural characterization, intermolecular energy calculations, solubility, and in vitro dissolution assessments.

Multistrain probiotic rescinds quinpirole-induced obsessive-compulsive disorder phenotypes by reshaping of microbiota gut-brain axis in rats.

Obsessive-compulsive disorder (OCD) is a disabling mental condition that poses recurring bothersome intrusive thoughts, obsessions, and compulsions. Considering the positive impact of probiotics on neuropsychiatric disorders, herein, we investigated the effect of multistrain probiotic (Bifidobacterium lactis UBBLa-70, Bacillus coagulans Unique IS-2, Lactobacillus rhamnosus UBLR-58, Lactobacillus plantarum UBLP-40, Bifidobacterium infantis UBBI-01, Bifidobacterium breve UBBr-01, and glutamine) in the management of OCD-like phenotype in rats. Rats injected with quinpirole for 5 weeks showed an increased number of marble burying and self-grooming episodes. Quinpirole-injected animals also did less head dipping in the hole board test and avoided exploration of open spaces in the elevated-plus maze. These repetitive, compulsive, self-directed, and anxiety-like phenotypes were abolished after 8-week of multistrain probiotic treatment. The probiotic formulation also prevented the elevated mRNA expression of interleukin-6, tumor-necrosis factor-α, and C-reactive protein in the amygdala and dysregulated levels of 5-hydroxytryptamine, dopamine, and noradrenaline in the frontal cortex of quinpirole-injected rats. The level of brain-derived neurotrophic factor in the frontal cortex remained unaffected across the groups. The altered levels of goblet cells and crypt-to-villi ratio in quinpirole rats were prevented by multistrain probiotic treatment. The results of 16S-rRNA gene-sequencing of gut microbiota from feces contents revealed an elevation in the abundance of Allobaculum and Bifidobacterium species (specifically Bifidobacterium animalis), while the presence of Lactobacillus species (including Lactobacillus reuteri and Lactobacillus vaginalis) exhibited a decline in quinpirole-induced rats. These results imply that modifying the gut-brain axis may be a possible mechanism by which selective multistrain probiotic therapy prevents OCD-like behaviors.

Multistrain Probiotics with Fructooligosaccharides Improve Middle Cerebral Artery Occlusion-Driven Neurological Deficits by Revamping Microbiota-Gut-Brain Axis.

Recent burgeoning literature unveils the importance of gut microbiota in the neuropathology of post-stroke brain injury and recovery. Indeed, ingestion of prebiotics/probiotics imparts positive effects on post-stroke brain injury, neuroinflammation, gut dysbiosis, and intestinal integrity. However, information on the disease-specific preference of selective prebiotics/probiotics/synbiotics and their underlying mechanism is yet elusive. Herein, we examined the effect of a new synbiotic formulation containing multistrain probiotics (Lactobacillus reuteri UBLRu-87, Lactobacillus plantarum UBLP-40, Lactobacillus rhamnosus UBLR-58, Lactobacillus salivarius UBLS-22, and Bifidobacterium breve UBBr-01), and prebiotic fructooligosaccharides using a middle cerebral artery occlusion (MCAO) model of cerebral ischemia in female and male rats. Three weeks pre-MCAO administration of synbiotic rescinded the MCAO-induced sensorimotor and motor deficits on day 3 post-stroke in rotarod, foot-fault, adhesive removal, and paw whisker test. We also observed a decrease in infarct volume and neuronal death in the ipsilateral hemisphere of synbiotic-treated MCAO rats. The synbiotic treatment also reversed the elevated levels/mRNA expression of the glial fibrillary acidic protein (GFAP), NeuN, IL-1ß, TNF-α, IL-6, matrix metalloproteinase-9, and caspase-3 and decreased levels of occludin and zonula occludens-1 in MCAO rats. 16S rRNA gene-sequencing data of intestinal contents indicated an increase in genus/species of Prevotella (Prevotella copri), Lactobacillus (Lactobacillus reuteri), Roseburia, Allobaculum, and Faecalibacterium prausnitzii, and decreased abundance of Helicobacter, Desulfovibrio, and Akkermansia (Akkermansia muciniphila) in synbiotic-treated rats compared to the MCAO surgery group. These findings confer the potential benefits of our novel synbiotic preparation for MCAO-induced neurological dysfunctions by reshaping the gut-brain-axis mediators in rats.

Naringenin-Capped Silver Nanoparticles Amalgamated Gel for the Treatment of Cutaneous Candidiasis.

The current research was aimed to synthesize a phytomolecule, naringenin (NRG)-mediated silver nanoparticles (NRG-SNPs) to study their antifungal potential against Candida albicans (C. albicans) and Candida glabrata (C. glabrata). The NRG-SNPs were synthesized by using NRG as a reducing agent. The synthesis of NRG-SNPs was confirmed by a color change and surface plasmon resonance (SPR) peak at 425 nm. Furthermore, the NRG-SNPs were analyzed for size, PDI, and zeta potential, which were found to be 35 ± 0.21 nm, 0.19 ± 0.03, and 17.73 ± 0.92 mV, respectively. In silico results demonstrated that NRG had a strong affinity towards the sterol 14α-demethylase. The docking with ceramide revealed the skin permeation efficiency of the NRG-SNPs. Next, the NRG-SNPs were loaded into the topical dermal dosage form (NRG-SNPs-TDDF) by formulating a gel using Carbopol Ultrez 10 NF. The MIC50 of NRG solution and TSC-SNPs against C. albicans was found to be 50 µg/mL and 4.8 µg/mL, respectively, significantly (P < 0.05) higher than 0.3625 µg/mL of NRG-SNPs-TDDF. Correspondingly, MIC50 results were calculated against C. glabrata and the results of NRG, TSC-SNPs, NRG-SNPs-TDDF, and miconazole nitrate were found to be 50 µg/mL, 9.6 µg/mL, 0.3625 µg/mL, and 3-µg/mL, respectively. Interestingly, MIC50 of NRG-SNPs-TDDF was significantly (P < 0.05) lower than MIC50 of miconazole nitrate against C. glabrata. The FICI (fractional inhibitory concentration index) value against both the C. albicans and C. glabrata was found to be 0.016 and 0.011, respectively, which indicated the synergistic antifungal activity of NRG-SNPs-TDDF. Thus, NRG-SNPs-TDDF warrants further in depth in vivo study under a set of stringent parameters for translating in to a clinically viable antifungal product.

The Relevance of Experimental Charge Density Analysis in Unraveling Noncovalent Interactions in Molecular Crystals.

The work carried out by our research group over the last couple of decades in the context of quantitative crystal engineering involves the analysis of intermolecular interactions such as carbon (tetrel) bonding, pnicogen bonding, chalcogen bonding, and halogen bonding using experimental charge density methodology is reviewed. The focus is to extract electron density distribution in the intermolecular space and to obtain guidelines to evaluate the strength and directionality of such interactions towards the design of molecular crystals with desired properties. Following the early studies on halogen bonding interactions, several "sigma-hole" interaction types with similar electrostatic origins have been explored in recent times for their strength, origin, and structural consequences. These include interactions such as carbon (tetrel) bonding, pnicogen bonding, chalcogen bonding, and halogen bonding. Experimental X-ray charge density analysis has proved to be a powerful tool in unraveling the strength and electronic origin of such interactions, providing insights beyond the theoretical estimates from gas-phase molecular dimer calculations. In this mini-review, we outline some selected contributions from the X-ray charge density studies to the field of non-covalent interactions (NCIs) involving elements of the groups 14-17 of the periodic table. Quantitative insights into the nature of these interactions obtained from the experimental electron density distribution and subsequent topological analysis by the quantum theory of atoms in molecules (QTAIM) have been discussed. A few notable examples of weak interactions have been presented in terms of their experimental charge density features. These examples reveal not only the strength and beauty of X-ray charge density multipole modeling as an advanced structural chemistry tool but also its utility in providing experimental benchmarks for the theoretical studies of weak interactions in crystals.

Heterobicyclic inhibitors of transforming growth factor beta receptor I (TGFßRI).

The TGFß-TGFßR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFßR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFßRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T1/2 > 120 min) and significantly improved potency in the PSMAD cellular assay (IC50 = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFß-stimulated phospho-SMAD was observed in primary human T cells.

Hybrid molecules of carvacrol and benzoyl urea/thiourea with potential applications in agriculture and medicine.

Benzoyl phenyl urea, a class of insect growth regulator's acts by inhibiting chitin synthesis. Carvacrol, a naturally occurring monoterpenoid is an effective antifungal agent. We have structurally modified carvacrol (2-methyl-5-[1-methylethyl] phenol) by introducing benzoylphenyl urea linkage. Two series of benzoylcarvacryl thiourea (BCTU, 4a-f) and benzoylcarvacryl urea (BCU, 5a-f) derivatives were prepared and characterized by elemental analysis, IR, (1)H and (13)C NMR and Mass spectroscopy. Derivatives 4b, 4d, 4e, 4f and 5d, 5f showed comparable insecticidal activity with the standard BPU lufenuron against Dysdercus koenigii. BCTU derivatives 4c, 4e and BCU 5c showed good antifungal activity against phytopathogenic fungi viz. Magnaporthe grisae, Fusarium oxysporum, Dreschlera oryzae; food spoilage yeasts viz. Debaromyces hansenii, Pichia membranifaciens; and human pathogens viz. Candida albicans and Cryptococcus neoformans. Compounds 5d, 5e and 5f showed potent activity against human pathogens. Moderate and selective activity was observed for other compounds. All the synthesized compounds were non-haemolytic. These compounds have potential application in agriculture and medicine.

2-{[{2-Hy-droxy-3-[2-methyl-5-(propan-2-yl)phen-oxy]prop-yl}(pyridin-2-ylmeth-yl)amino]-meth-yl}phenol.

In the title racemic compound, C(26)H(32)N(2)O(3), an intra-molecular O-H⋯N hydrogen bond is formed between the phenolic OH group and the tertiary amine N atom. Another O-H⋯N hydrogen bond that is formed between the OH group and the pyridine N atom links the mol-ecules into a polymeric chain extending along the a axis. The structure is further stabilized by intramolecular and intermolecular C-H⋯O interactions.

Recognition of polycyclic aromatic hydrocarbons and their derivatives by the 1,3-dinaphthalimide conjugate of calix[4]arene: emission, absorption, crystal structures, and computational studies.

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants as well as well-known carcinogens. Therefore, it is important to develop an effective receptor for the detection and quantification of such molecules in solution. In view of this, a 1,3-dinaphthalimide derivative of calix[4]arene (L) has been synthesized and characterized, and the structure has been established by single crystal XRD. In the crystal lattice, intermolecular arm-to-arm π···π overlap dominates and thus L becomes a promising receptor for providing interactions with the aromatic species in solution, which can be monitored by following the changes that occur in its fluorescence and absorption spectra. On the basis of the solution studies carried out with about 17 derivatives of the aromatic guest molecular systems, it may be concluded that the changes that occur in the fluorescence intensity seem to be proportional to the number of aromatic rings present and thus proportional to the extent of π···π interaction present between the naphthalimide moieties and the aromatic portion of the guest molecule. Though the nonaromatic portion of the guest species affects the fluorescence quenching, the trend is still based on the number of rings present in these. Four guest aldehydes are bound to L with K(ass) of 2000-6000 M(-1) and their minimum detection limit is in the range of 8-35 µM. The crystal structure of a naphthaldehyde complex, L.2b, exhibits intermolecular arm-to-arm as well as arm-to-naphthaldehyde π···π interactions. Molecular dynamics studies of L carried out in the presence of aromatic aldehydes under vacuum as well as in acetonitrile resulted in exhibiting interactions observed in the solid state and hence the changes observed in the fluorescence and absorption spectra are attributable for such interactions. Complex formation has also been delineated through ESI MS studies. Thus L is a promising receptor that can recognize PAHs by providing spectral changes proportional to the aromatic conjugation of the guest and the extent of aromatic π···π interactions present between L and the guest.

A lower rim triazole linked calix[4]arene conjugate as a fluorescence switch on sensor for Zn2+ in blood serum milieu.

A fluorescence turn-on receptor based on triazole linked calix[4]arene (L) for selective recognition of Zn(2+) in aqueous-methanolic HEPES buffer has been developed and showed its utility for sensing Zn(2+) in blood serum milieu.

(Z)-2-(2-Isopropyl-5-methyl-phen-oxy)-N'-(2-oxoindolin-3-yl-idene)acetohydrazide.

In the title Mannich base, C(20)H(21)N(3)O(3), an isatin derivative of thymol, the O-CH(2)-C(=O)-N(H)-N fragment connect-ing the aromatic and fused-ring systems is approximately planar, with the N-N single bond in a Z configuration. The amino H atom of this N-N fragment is intra-molecularly hydrogen bonded to the carbonyl O atom of the indolinone fused ring as well as to the phen-oxy O atom of the aromatic ring. The amino H atom of the indoline fused ring forms a hydrogen bond with the double-bond O atom of an adjacent mol-ecule, this hydrogen bond giving rise to a linear chain motif.