Chemical composition, antioxidant, antimicrobial, and wound healing effects of Trachyspermum roxburghianum (DC.) H. Wolff essential oil: An in vivo and in silico approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Trachyspermum roxburghianum (DC.) H. Wolff, commonly known as 'Ajamoda,' is a neglected Indian spice highly used in Ayurveda and folklore remedies as an antimicrobial for chronic wounds and discharges, along with many other disease conditions. AIM OF THE STUDY: The objective of the study was to explore chemical composition and to investigate the antioxidant, antimicrobial, analgesic, and wound healing activities of T. roxburghianum fruit essential oil from India. MATERIALS AND METHODS: The phytochemical characterization of the oil was determined through standard qualitative procedures and the gas chromatography-mass spectrometry (GC-MS) technique. The in vitro antioxidant aptitude was assessed by scavenging DPPH and ABTS radicals. The antimicrobial potential of the oil was investigated using the disc diffusion method, followed by the determination of minimum inhibitory concentration against Gram-positive and Gram-negative bacterial and fungal strains. The analgesic potential was evaluated using thermal and chemically induced pain models in Swiss albino mice. Wound healing was assessed in vivo, including determining wound contraction rates, histopathology, and hydroxyproline estimation, using the excision wound model in Swiss albino mice. RESULTS: GC-MS analysis identified 55 compounds with major terpenoids, including thymol (13.8%), limonene (11.5%), and others. Substantial radical-scavenging activity was exhibited by T. roxburghianum fruit essential oil (TREO) (IC50 94.41 ± 2.00 µg/mL in DPPH assay and 91.28 ± 1.94 µg/mL in ABTS assay). Microorganisms were inhibited with low MIC (2 µL/mL for the inhibition of Staphylococcus aureus and Bacillus subtilis; 4 µL/mL against Salmonella typhi and 16 µL/mL against Candida albicans). In the cytotoxicity study, no cytotoxicity was observed on the Monkey Normal Kidney Cell line (Vero). Significant antinociceptive effects were observed (25.47 ± 1.10 % of inhibition at 100 mg/kg and 44.31 ± 1.69 % at 200 mg/kg). A remarkable rate of wound closure and epithelization, along with a marked increase in hydroxyproline content, were observed for the oil during wound healing in mice. CONCLUSIONS: The results suggested that oil could be utilized as a potential source of wound healing therapeutics.

Exploring film forming ability and improving its bioadhesiveness by thiolation of mucilaginous polysaccharides from Cassia uniflora seeds for drug delivery application.

The objectives of the present work were to explore film forming ability of mucilaginous polysaccharides obtained from Cassia uniflora seeds and improving its bioadhesive potential by thiolation for drug delivery and other applications. Thiolation was achieved by esterification reaction with thioglycolic acid. The modification was confirmed by performing and comparing its zeta potential, DSC, and spectrophotometric characterization by FTIR and NMR with unmodified mucilaginous polysaccharide. The modified mucilaginous polysaccharides FTIR spectra showed an additional absorption band at 2565 cm-1 and new shifts appeared in the 1H (δ 3.24 and at δ 3.44 ppm) and 13C NMR spectra's (21.56 ppm) confirming the esterification of mucilaginous polysaccharides. The prepared films of thiolated and unmodified mucilaginous polysaccharides were evaluated for various parameters like thickness, pH, and weight measurement, The film formulation had a thickness of 0.16 to 0.18 mm, pH in the range of 6.79 to 7.09 and weight uniformity 0.89 to 0.94 mg. The results reveal that the films based on thiolated material improved bioadhesive properties after thiolation. The SEM photographs revealed a smooth surface of film formulations. The diclofenac-loaded film of thiolated mucilaginous polysaccharide also showed >1.5-fold an increase in in-vitro drug release and exhibited non Fickian transport mechanism. These findings could increase the possible applications of chemically modified-thiolated mucilaginous polysaccharides of Cassia uniflora seeds in drug delivery.

Chemical composition and biological activities of Lonicera caprifolium L. (Caprifoliaceae) essential oil.

This work aimed to investigate the chemical composition, antioxidant activity, antinociceptive effect, and wound healing activity of the Lonicera caprifolium L. flower essential oil (LCEO). Linalool (16.42%), d-limonene (9.99%), and α-cadinol (10.65%) were the most prevalent components of the LCEO. The LCEO revealed moderate DPPH and ABTS radical-scavenging activity. LCEO exhibited potent antinociceptive activity in acetic acid-induced writhing and hot plate-induced pain model; LCEO reduced 73.88 ± 2.78% of writhing and significantly increased pain withdrawal latency in the mice, respectively. The LCEO also presented a potent wound healing effect, with 98.08 ± 1.37% wound closure on the 12th day of treatment. The results of the study demonstrate antioxidant and wound healing potential with antinociceptive effect. To the best of our knowledge, this is the first report on the bioactivities of L. caprifolium L. essential oil.

Isolation and Characterization of Anti-Inflammatory Compounds from Ficus microcarpa L.f. Stem Bark.

The anti-inflammatory effect of the ethyl acetate extract of F. microcarpa bark (EAFMB) was investigated in acute and chronic (21 days) inflammation induced in Wistar albino rats. EAFMB (200 mg/kg b.w.) exhibited comparable anti-inflammatory effects to the reference drug, with a reduction of 59.48% at 4 h in acute inflammation and 83.96% on day 21 in chronic inflammation. Bioassay-guided fractionation using DPPH radical scavenging activity led to isolating and identifying three compounds from EAFMB: oleanolic acid, catechin, and p-hydroxycinnamic acid. All these compounds demonstrated the concentration-dependent inhibition of COX enzymes and the protection of egg albumin from heat-induced denaturation. Catechin exhibited the highest COX inhibition (COX-1 and COX-2 IC50 = 9.02 and 50.38 µM, respectively) and anti-denaturation effect (IC50 = 27.13 µg/mL) compared to oleanolic acid and p-hydroxycinnamic acid. These isolated compounds are likely responsible for the anti-inflammatory activities of F. microcarpa bark.

Quality-by-design based fabrication of febuxostat-loaded nanoemulsion: Statistical optimization, characterizations, permeability, and bioavailability studies.

The present work deals with QbD-based development of FEB-loaded nanoemulsion (FEB-NE) in order to enhance bioavailability and permeability. In the beginning, the risk assessment was performed on different experimental variables using the Ishikawa diagram followed by FMEA study in order to find critical process parameter (CPP) and critical material attributes (CMAs). To build quality in nanoemulsion, the quality target product profiles (QTPP) and critical quality attributes (CQAs) were determined. The different batches of FEB-NE were produced by the microemulsification-probe sonication method. Effect of varying levels of independent variables such as oil concentration (X1), Smix concentration (X3), and amplitude (X3) on responses such as globule size (Y1), zeta potential (Y2), and entrapment efficiency (Y3) were studied using Box-Behnken design (BDD). FEB-NE formulation was optimized using a graphical and numerical method. The optimized formulation concentrations and their responses (CQAs) were located as design space in an overlay plot. The spherical shapes of globules were visualized by surface morphology using AFM and TEM. In vitro dissolution study showed 93.32% drug release from the optimized FEB-NE formulation. The drug release mechanism followed by the formulation was the Higuchi-matrix kinetics with a regression coefficient of 0.9236 (R2). FEB-NE showed enhanced permeability using PAMPA (artificial non-cell membrane) and everted gut sac model method. The developed optimized FEB-NE exhibited the enhancement of bioavailability by 2.48 fold as compared to FEB-suspension using Wistar rats suggesting improvement of solubility of a lipophilic drug. The optimized batch remained stable for 90 days at 4 °C and 25 °C. Thus, QbD-based development of FEB-NE can be useful for a better perspective on a commercial scale.

Phytochemical profile, antioxidant, cytotoxic and anti-inflammatory activities of stem bark extract and fractions of Ailanthus excelsa Roxb.: In vitro, in vivo and in silico approaches.

This study aimed to assess the phytochemical composition, in vitro antioxidant, cytotoxicity, and in vivo anti-inflammatory activities of the methanolic extract of Ailanthus excelsa (Simaroubaceae) stem bark and its fractions. Quantitative phytochemical analysis revealed that methanolic extract and all fractions contained a high level of flavonoids (20.40-22.91 mg/g QE), phenolics (1.72-7.41 mg/g GAE), saponins (33.28-51.87 mg/g DE), and alkaloids (0.21-0.33 mg/g AE). The antioxidant potential was evaluated in vitro using a range of assays, i.e., DPPH•, ABTS radical scavenging ability, and total antioxidant capacity. The chloroform and ethyl acetate fractions showed stronger antioxidant activity than the methanol extract. In vitro cytotoxic activity was investigated in three human tumor cell lines (A-549, MCF7 and HepG2) using the SRB assay. In addition, the in vivo anti-inflammatory effect was assessed by carrageenan-induced paw edema in rats. The chloroform fraction showed a more pronounced effect by effectively controlling the growth with the lowest GI50 and TGI concentrations. The human lung cancer cell line (A-549) was found to be more sensitive to the chloroform fraction. Furthermore, the chloroform fraction exhibited significant anti-inflammatory activity at a dose of 200 mg/kg in the latter phase of inflammation. Besides, methanol extract and ethyl acetate fraction revealed a significant cytotoxic and anti-inflammatory effects. The chloroform fraction of stem bark showed a strong anti-inflammatory effect in experimental animals and significant COX-2 inhibitory potential in the in vitro experiments. GC-MS analysis of chloroform fraction identified the phytochemicals like caftaric acid, 3,4-dihydroxy phenylacetic acid, arachidonic acid, cinnamic acid, 3-hydroxyphenylvaleric acid, caffeic acid, hexadeconoic acid, and oleanolic acid. The in-silico results suggest that identified compounds have better affinity towards the selected targets, viz. the BAX protein (PDB ID: 1F16), p53-binding protein Mdm-2 (PDB ID: 1YCR), and topoisomerase II (PDB ID: 1QZR). Amongst all, caftaric acid exhibited the best binding affinity for all three targets. Thus, it can be concluded that caftaric acid in combination with other phenolic compounds, might be responsible for the studied activity. Additional in vivo and in vitro studies are required to establish their exact molecular mechanisms and consider them as lead molecules in developing of valuable drugs for treating oxidative stress-induced disorders, cancers, and inflammations.

Sulfobutylether-ß-cyclodextrin: A functional biopolymer for drug delivery applications.

Sulfobutylether ß-cyclodextrin (SBE-ß-CD) is a polyanionic cyclic oligosaccharide that contains glucopyranose units forming a torus ring-like structure. SBE-ß-CD is gifted with many favorable properties viz. relatively high solubility (>50 folds compared to ß-CD), improved stability, and biocompatibility that praised SBE-ß-CD as a smart polymer for drug delivery applications. Commercially, SBE-ß-CD is popular by its brand name Captisol®. The present review discusses the structure, properties, and preparation methods of SBE-ß-CD-based inclusion complexes (ICs). Furthermore, we discuss here the preparation and applications of SBE-ß-CD ICs-based nanoparticulate drug delivery systems, which combines the merits of both, ICs (enhanced solubility) and nanoparticles (NPs, targeted therapy). Patents on and FDA-approved Captisol®-enabled products are tabulated in the benefit of readers. The toxicological aspects and current clinical status of SBE-ß-CD or SBE-ß-CD-based products are briefly explained in the present review. In our opinion, the present review would be a pathfinder to allow dissemination of information on SBE-ß-CD.

Synthesis, Molecular Modeling Study, and Quantum-Chemical-Based Investigations of Isoindoline-1,3-diones as Antimycobacterial Agents.

The condensation of phthalic anhydride afforded structurally modified isoindoline-1,3-dione derivatives with selected amino-containing compounds. The title compounds (2-30) have been characterized by thin-layer chromatography (TLC), infrared spectroscopy, 1H and 13C NMR spectroscopy, and mass spectroscopy. All of the compounds were assessed for their antimycobacterial activity toward the H37Rv strain by a dual read-out assay method. Among the synthesized compounds, compound 27 possessed a significant IC50 of 18 µM, making it the most potent compound of the series. The InhA inhibitory (IC50) activity of compound 27 was 8.65 µM in comparison to Triclosan (1.32 µM). Computational studies like density functional theory (DFT) study, molecular docking, and dynamic simulation studies illustrated the reactivity and stability of the synthesized compounds as InhA inhibitors. A quantum-mechanics-based DFT study was carried out to investigate the molecular and electronic properties, reactivities, and nature of bonding present in the synthesized compounds and theoretical vibrational (IR) and isotropic value (1H and 13C NMR) calculations.

Discovery and Anticancer Activity of Novel 1,3,4-Thiadiazole- and Aziridine-Based Indolin-2-ones via In Silico Design Followed by Supramolecular Green Synthesis.

Three crucial anticancer scaffolds, namely indolin-2-one, 1,3,4-thiadiazole, and aziridine, are explored to synthesize virtually screened target molecules based on the c-KIT kinase protein. The stem cell factor receptor c-KIT was selected as target because most U.S. FDA-approved receptor tyrosine kinase inhibitors bearing the indolin-2-one scaffold profoundly inhibit c-KIT. Molecular hybrids of indolin-2-one with 1,3,4-thiadiazole (IIIa-m) and aziridine (VIa and VIc) were afforded through a modified Schiff base green synthesis using ß-cyclodextrin-SO3H in water as a recyclable proton-donor catalyst. A computational study found that indolin-2,3-dione forms a supramolecular inclusion complex with ß-cyclodextrin-SO3H through noncovalent interactions. A molecular docking study of all the synthesized compounds was executed on the c-KIT kinase domain, and most compounds displayed binding affinities similar to that of Sunitinib. On the basis of the pharmacokinetic significance of the aryl thioether linkage in small molecules, 1,3,4-thiadiazole hybrids (IIIa-m) were extended to a new series of 3-((5-(phenylthio)-1,3,4-thiadiazol-2-yl)imino)indolin-2-ones (IVa-m) via thioetherification using bis(triphenylphosphine)palladium(II)dichloride as the catalyst for C-S bond formation. Target compounds were tested against NCI-60 human cancer cell lines for a single-dose concentration. Among all three series of indolin-2-ones, the majority of compounds demonstrated broad-spectrum activity toward various cancer cell lines. Compounds IVc and VIc were further evaluated for a five-dose anticancer study. Compound IVc showed a potent activity of IC50 = 1.47 µM against a panel of breast cancer cell lines, whereas compound VIc exhibited the highest inhibition for a panel of colon cancer cell lines at IC50 = 1.40 µM. In silico ADME property descriptors of all the target molecules are in an acceptable range. Machine learning algorithms were used to examine the metabolites and phase I and II regioselectivities of compounds IVc and VIc, and the results suggested that these two compounds could be potential leads for the treatment of cancer.

Development and Optimization of Vitamin D3 Solid Self-Microemulsifying Drug Delivery System: Investigation of Flowability and Shelf Life.

We report herein the design of a solid self-microemulsifying drug delivery system (SMEDDS) of vitamin D3 for augmentation of its solubility and dissolution. The studies employed a 32 full factorial design by employing JMP 13.2.1, software for preparation of liquid SMEDDS. Further, the prediction profiler was utilized to optimized liquid SMEDDS-Vit.D3 (OF) formulation. The solidification of liquid SMEDDS-Vit.D3 formulation was carried out by physical adsorption over Neusilin US2 and Aerosil 200 carriers. Solid-state evaluation of SMEDDS-Vit.D3 suggested the transformation of crystalline to amorphous form of Vit.D3 which is responsible for imparting more aqueous solubility and thus enhancement in dissolution behaviour. The investigation of flow behaviours viz. flow function (FF) and effective angle of wall friction (EAWF) of solid SMEDDS-Vit.D3 was performed using powder flow tester. Solid SMEDDS-Vit.D3 prepared using Neusilin US2 showed good flow behaviour and hence was developed into tablets. The tablets showed good quality control parameters as per pharmacopeial standards. The in vitro dissolution studies demonstrated more dissolution of Vit.D3 in SMEDDS (liquid, solid, and tablet) when compared to the unprocessed drug. The shelf life (T90) of tablets was reported to be 28.12 months suggesting excellent stability of Vit.D3 in solid SMEDDS. In nutshell, our research works explore the utilization of SMEDDS for the oral delivery of Vit.D3 to gain maximum health-related benefits.

Phytochemical and pharmacological validation of folklore medicine practiced in south-western Satpuda Ranges (India) for management of inflammatory conditions.

INTRODUCTION: The ethnobotanical survey of the South-western Satpuda ranges has continued for decades. However, very few disease-specific surveys and their pharmacological validation have been published. The present study aimed to identify, document, and pharmacologically validate the tribal knowledge on anti-inflammatory medicinal plants. METHODS: The field survey was conducted over a year from July 2015 to June 2016, scattered in the South-Western region of Satpuda Ranges. Documentation and identification of the medicinal herbs used often in the treatment of inflammatory conditions. Two plants, namely Eulophia herbacea Lindl., and Grewia flavescens A. Juss. were commonly used for inflammatory conditions. Phytopharmacological validation was done using carrageenan induced inflammation and CFA-induced arthritis. RESULTS: The current investigation identified 32 plants from 22 different families as anti-inflammatory plants. G. flavescens exhibited substantial antiarthritic action in complete Freund's adjuvant-induced arthritis in rats, and E. herbacea showed powerful anti-inflammatory activity in carrageenan-induced rat paw edema model. This activity might be attributed to the presence of gallic acid, quercetin, ß-sitosterol and lupeol. CONCLUSION: The research reveals that selected plants had anti-inflammatory properties in both acute and chronic inflammation. Further studies to highlight the exact mechanism of action of these plants are warranted.

Investigating the Impact of Different Acrylamide (Electrophilic Warhead) on Osimertinib's Pharmacological Spectrum by Molecular Mechanic and Quantum Mechanic Approach.

BACKGROUND: Lung cancer has become the prominent cause of the cancer-related deaths globally. More than 80 % of all lung cancers have been diagnosed with Non- Small Cell Lung Cancer (NSCLC). The USFDA approved osimertinib to treat patients with metastatic T790M EGFR NSCLC on a regular basis in March 2017. Recently, C797S mutation to osimertinib has been reported, which indicates the need for structural modification to overcome the problem of mutation. METHODS: In this bioinformatics study, we have evaluated the impact of various acrylamide as an electrophilic warhead on the activity and selectivity of osimertinib. RESULT: Osimertinib analouge 48, 50, 60, 61, 67, 75, 80, 86, 89, 92, 93, 116 and 124 were the most active and selective compounds against T790M EGFR mutants compared to Osimertinib. CONCLUSION: These compounds also showed less inclination towards WT-EGFR.

p38α MAP kinase inhibitors to overcome EGFR tertiary C797S point mutation associated with osimertinib in non-small cell lung cancer (NSCLC): emergence of fourth-generation EGFR inhibitor.

The third-generation EGFR (epidermal growth factor receptor) inhibitors selectively and irreversibly target EGFR-T790M and other activating EGFR mutations. Osimertinib is the only FDA-approved third-generation inhibitor, which has a good potency against the EGFR-T790M mutant with minimal toxicities and excellent selectivity for wild-type EGFR. EGFR tertiary Cys797 to Ser797 (C797S) point mutation emanate rapidly after the treatment of osimertinib, which is an undruggable mutation to all three existing generation drugs. Recently, trisubstituted imidazoles were reported based on an off-target hit of a p38α MAPK (mitogen-activated protein kinase) inhibitor as the fourth-generation EGFR-TKIs to overcome the C797S resistance by inhibiting the clinically relevant triple mutant kinase L858R/T790M/C797 EGFR. Here, we are reporting the clinical trial p38α MAPK kinase inhibitors SD-06, Amgen 16, RWJ67657 and SCIO-323 as L858R/T790M/C797S EGFR TK inhibitors to overcome the problem of drug resistance in non-small cell lung cancer (NSCLC).Communicated by Ramaswamy H. Sarma.

Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer.

The pyrimidine core-containing compound Osimertinib is the only epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the third generation that has been approved by the U.S. Food and Drug Administration to target threonine 790 methionine (T790M) resistance while sparing the wild-type epidermal growth factor receptor (WT EGFR). It is nearly 200-fold more selective toward the mutant EGFR as compared to the WT EGFR. A tertiary cystein 797 to serine 797 (C797S) mutation in the EGFR kinase domain has hampered Osimertinib treatment in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). This C797S mutation is presumed to induce a tertiary-acquired resistance to all current reversible and irreversible EGFR TKIs. This review summarizes the molecular mechanisms of resistance to Osimertinib as well as different strategies for overcoming the EGFR-dependent and EGFR-independent mechanisms of resistance, new challenges, and a future direction.

Computational identification of 2,4-disubstituted amino-pyrimidines as L858R/T790M-EGFR double mutant inhibitors using pharmacophore mapping, molecular docking, binding free energy calculation, DFT study and molecular dynamic simulation.

Pharmacophore modelling studies have been performed for a series of 2,4-disubstituted-pyrimidines derivatives as EGFR L858R/T790M tyrosine kinase inhibitors. The high scoring AARR.15 hypothesis was selected as the best pharmacophore model with the highest survival score of 3.436 having two hydrogen bond acceptors and two aromatic ring features. Pharmacophore-based virtual screening followed by structure-based yielded the six molecules (ZINC17013227, ZINC17013215, ZINC9573324, ZINC9573445, ZINC24023331 and ZINC17013503) from the ZINC database with significant in silico predicted activity and strong binding affinity towords the EGFR L858R/T790M tyrosine kinase. In silico toxicity and cytochrome profiling indicates that all the 06 virtually screened compounds were substrate/inhibitors of the CYP-3A4 metabolizing enzyme and were non-carcinogenic and devoid of Ames mutagenesis. Density functional theory (DFT) and molecular dynamic (MD) simulation further validated the obtained hits. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00113-x.

The Repurposed ACE2 Inhibitors: SARS-CoV-2 Entry Blockers of Covid-19.

The highly infectious disease COVID-19 is induced by SARS-coronavirus 2 (SARS-CoV-2), which has spread rapidly around the globe and was announced as a pandemic by the World Health Organization (WHO) in March 2020. SARS-CoV-2 binds to the host cell's angiotensin converting enzyme 2 (ACE2) receptor through the viral surface spike glycoprotein (S-protein). ACE2 is expressed in the oral mucosa and can therefore constitute an essential route for entry of SARS-CoV-2 into hosts through the tongue and lung epithelial cells. At present, no effective treatments for SARS-CoV-2 are yet in place. Blocking entry of the virus by inhibiting ACE2 is more advantageous than inhibiting the subsequent stages of the SARS-CoV-2 life cycle. Based on current published evidence, we have summarized the different in silico based studies and repurposing of anti-viral drugs to target ACE2, SARS-CoV-2 S-Protein: ACE2 and SARS-CoV-2 S-RBD: ACE2. This review will be useful to researchers looking to effectively recognize and deal with SARS-CoV-2, and in the development of repurposed ACE2 inhibitors against COVID-19.

Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC).

T790M mutation is the most common mechanism of acquired resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed. However, the clinical application of these irreversible inhibitors is limited due to its narrow selectivity against L858R/T790M mutant EGFR. In an attempt to develop potent and selective EGFR T790M inhibitors, we have designed and synthesized two series of novel acrylamide linked quinazolines. Among them, compounds 2i (IC50 0.171 µM) and 11h (IC50 0.159 µM) were identified as potent compounds, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975 as compared to the gefitinib and WZ4002 in cellular assay. Furthermore, a molecular dynamic simulation of 11h was carried out to assess the stability to form a complex with the L858R/T790M EGFR Kinase domain, which demonstrated that complex was stable for the 100 ns and form strong crucial covalent binding contacts with the thiol group of Cys797 residue. Finally, satisfactory in silico pharmacokinetics properties of 2i, 11h and 11i compounds were predicted. The synthesized compounds were also evaluated for in vitro cytotoxic activity/hepatotoxicity against HepG2 cell line through MTT assay. The results revealed that compounds exhibited lower cytotoxicity to HepG2 cells.

The Mur Enzymes Chink in the Armour of Mycobacterium tuberculosis cell wall.

TUBERCULOSIS: (TB) transmitted by Mycobacterium tuberculosis (Mtb) is one of the top 10 causes of death globally. Currently, the widespread occurrence of resistance toward Mtb strains is becoming a significant concern to public health. This scenario exaggerated the need for the discovery of novel targets and their inhibitors. Targeting the "Mtb cell wall peptidoglycan synthesis" is an attractive strategy to overcome drug resistance. Mur enzymes (MurA-MurF) play essential roles in the peptidoglycan synthesis by catalyzing the ligation of key amino acid residues to the stem peptide. These enzymes are unique and confined to the eubacteria and are absent in humans, representing potential targets for anti-tubercular drug discovery. Mtb Mur ligases with the same catalytic mechanism share conserved amino acid regions and structural features that can conceivably exploit for the designing of the inhibitors, which can simultaneously target more than one isoforms (MurC-MurF) of the enzyme. In light of these findings in the current review, we have discussed the recent advances in medicinal chemistry of Mtb Mur enzymes (MurA-MurF) and their inhibitors, offering attractive multi-targeted strategies to combat the problem of drug-resistant in M. tuberculosis.

Electrostatic deposition assisted preparation, characterization and evaluation of chrysin liposomes for breast cancer treatment.

Chrysin (CHR), a flavone found in multiple vegetables, fruits and mushrooms has been explored so far as a neurotropic, anti-inflammatory and anti-cancer biomolecule. Despite the stated therapeutic potential, low solubility and bioavailability limit its therapeutic benefit. To circumvent these drawbacks, development of chrysin liposomes (CLPs) is reported in the present investigation. The CLPs were developed by electrostatic deposition assisted film hydration method using chitosan/lecithin to protect chrysin in the nano-lipoidal shell. Developed CLPs were extensively characterized by DSC, XPRD, FE-SEM, TEM, particle size, polydispersity index, zeta potential, percent drug loading and encapsulation efficiency. These CLPs were further characterized by in vitro dissolution, in vivo bioavailability, in vitro anticancer and stability study. Suitable particle size, PDI and ZP implying stabilization of developed CLPs. The % DL and % EE was found to be 3.56 ± 0.13 and 90.5 ± 1.49 respectively. DSC and PXRD study revealed amorphous transition of CHR, which may help to increase its solubility and dissolution profile. In vivo pharmacokinetic study demonstrated more than 5-fold increase in relative bioavailability of CLPs. The in silico molecular docking study results demonstrated the electrostatic interaction between two polymers. The present study suggests that chitosan could protect and encapsulate chrysin which eventually enhances its cytotoxicity as well as bioavailability.

Development and statistical optimization of alginate-Neusilin US2 micro-composite beads to elicit gastric stability and sustained action of hesperidin.

The Alginate-Neusilin US2 micro-composite (MC) beads were fabricated and optimized for oral delivery of hesperidin (HES). A 32 full factorial design encompassing independent variables (factors) such as the concentration of sodium alginate (X1), and Neusilin US2 (X2) and dependant variables (response) such as particle size (Y1), entrapment efficiency (Y2), and swelling degree (Y3). Nine batches were prepared by formulation design employing statistical software JMP 13.2.1. The multiple regression analysis (MLRA) was carried to explore the influence of factor over responses. Further, a prediction profiler was used to trace the optimum concentration of factors based on desirable responses. The optimized beads (OF) were characterized for their morphology and size by motic microscopy and scanning electron microscopy. In vitro release, kinetic studies were performed in simulated gastric and intestinal fluids. In vivo pharmacokinetic studies revealed better absorption of HES from optimized beads (OF) compared to HES suspension which could be due to the prevention of acidic degradation of HES in the stomach. The estimated shelf life of OF formulation was found to be 3.86 years suggested better stability after fabrication. In a nutshell, the developed micro-composite beads of HES could be a better alternative for promising oral sustained delivery of HES.