The persistent global burden of viral diseases, exemplified by endemic infections and pandemic outbreaks such as COVID-19, underscores the critical need for effective antiviral therapies. While current agents such as nucleoside analogs and direct-acting antivirals (DAAs) have improved the treatment of infections like HIV, hepatitis C, and influenza, they face limitations including narrow target specificity, resistance development, and adverse effects. These challenges are intensified by the rise of emerging zoonotic viruses driven by climate change, globalization, and urbanization, creating an urgent demand for broad-spectrum antivirals with novel mechanisms of action. Mannich base (MB) derivatives have emerged as promising scaffolds in antiviral drug discovery due to their synthetic accessibility, structural diversity, and ability to enhance solubility, permeability, and bioactivity. In addition to these advantages, MBs exhibit broad-spectrum antiviral activity through unique mechanisms, including viral fusion inhibition and allosteric modulation of viral polymerases, distinguishing them from traditional antivirals and offering potential solutions to resistance. Their capacity to target both RNA and DNA viruses further underscores their therapeutic promise. Recent studies have demonstrated the antiviral efficacy of MBs against a wide range of viruses, including yellow fever virus (YFV), respiratory syncytial virus (RSV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), bovine viral diarrhea virus (BVDV), influenza A, and SARS-CoV-2. Structure–activity relationship (SAR) analyses have highlighted the importance of core scaffolds, ring substitutions, amine types, substitution sites, and linker flexibility in modulating antiviral activity. Electron-withdrawing groups (e.g., Cl, Br, NO2, F) generally enhance potency, while electron-donating groups such as OCH3 have shown variable effects. This review presents a comprehensive analysis of MB-based antivirals developed over the past two decades, with a focus on SAR insights, mechanistic understanding, and their potential in next-generation antiviral development.

Objective: The present study was to formulate and evaluate a solid self-nanoemulsifying drug delivery system (SNEDDS) for Mesalamine. Mesalamine was classified as BCS IV, exhibits limited solubility and permeability. Methods: The formulation of liquid SNEDDS was constructed by a pseudoternary phase diagram, which was optimized by the application of a Box-Behnken experimental design. Liquid SNEDDS were then prepared using oleic acid, Tween 80, and PEG 200 at concentrations given by design of experiments (DoE). The liquid SNEDDS were subsequently converted into solid SNEDDS by adsorption technique using Aerosil 200 as the adsorbent agent. The solid SNEDDS were filled into hard gelatine capsules, and further characterization was carried out. Results: The formulated SNEDDS has a zeta potential of -17 mV and a mean globule size of 107 nm. The efficacy of the formulation was verified by dispersibility, dilution, viscosity, drug content analysis, % transmittance, dye solubility, cloud point, and in vitro drug release studies. The solid SNEDDS underwent physical and micromeritic property evaluations, in vitro dissolution studies, and morphological characterization via Field Emission Scanning Electron Microscopy (FE-SEM). Solid-state characterization showed that Mesalamine was dissolved in the matrix system by (DSC), existed in an amorphous state (PXRD), and had well-separated particles (FE-SEM). The in vitro dissolution study revealed that the optimized SNEDDS had a higher drug release rate than plain Mesalamine. Conclusion: The study concluded that solid SNEDDS improved solubility, absorption, and permeability of Mesalamine, suggesting enhanced drug delivery and therapeutic efficacy.

Background: Inflammation, a complex biological process mediated by arachidonic acid metabolites, plays a crucial role in various diseases like arthritis, psoriasis and neurodegenerative disorders. The Cyclooxygenase (COX) pathway, particularly COX-2, is a well-established anti-inflammatory target. Materials and Methods: This study aimed to discover and evaluate novel pyrazole derivatives as potential COX-2 inhibitors via virtual screening. The 3D crystal structure of Cyclooxygenase-II (PDB: 1CX2) was prepared and optimized for in-silico investigations. Molecular docking analysis using AutoDock Vina assessed ligand-protein interactions, guided by CASTp3.0-predicted binding sites. Ligands were energy minimized and docked against the protein and drug-likeness/synthetic accessibility was predicted using SwissADME and pkCSM. Biological activity and medicinal chemistry were assessed using network diagrams, Bioavailability Radar and BOILED-Egg model for absorption and brain penetration prediction. This integrated approach facilitates the identification of potential COX-2 inhibitors with favorable pharmacokinetic profiles for further development. Results: Through molecular docking, three compounds (D202, D305 and F505) exhibited the highest binding affinity for COX-2, surpassing the native ligand's residual binding. Subsequent ADMET prediction revealed promising pharmacokinetic properties, including significant oral bioavailability scores (0.55) and synthetic feasibility scores ranging from 3.05 to 3.74. Conclusion: These findings suggest the potential of these pyrazole derivatives as promising lead candidates for further development as novel anti-inflammatory agents.

Polyherbal extracts (PHEs), known for managing diabetes by supporting liver and pancreas health, face challenges such as poor solubility, bioavailability, and stability, which hinder their effectiveness. This study aims to enhance the efficacy of PHEs through the development of a self-microemulsifying drug delivery system (SMEDDS). Plants including Berberis aristata, Picrorhiza kurroa, and Boerhaavia diffusa for hepatoprotective effects; Pterocarpus marsupium, Holarrhena antidysentrica, and Eugenia jambolana for pancreatic protection; Cassia angustifolia for purgative action; and Rubia cordifolia for blood purification were used, combined in different proportions, extracted using Soxhlet extraction, and evaluated. The solubilities of PHEs were determined in oils, surfactants, and cosurfactants, selecting soybean oil, Span 80:Tween 80 (2:1), and ethanol. A central composite design optimized SMEDDS, examining oil (10-20 %) and surfactant (40-50 %) effects on globule size and zeta potential. Characterization utilized DLS, DSC, SEM, PXRD, TEM, GCMS, and HPTLC. GCMS and HPTLC analysis confirmed the entrapment of PHE within SMEDDS, while DSC and XRD studies corroborated partial amorphization of PHE in SMEDDS. In vivo studies on Wistar rats showed that optimized SMEDDS, with a globule size of 378.6 nm and zeta potential of -31.8 mV, demonstrated superior effectiveness compared to the extract alone and standard glibenclamide treatment, particularly at higher doses (500 mg/kg). SMEDDS improved biochemical markers, lipid profiles, and antioxidant enzyme activities, indicating significant protective effects on liver and pancreatic tissues. These results highlight the potential of PHE-SMEDDS as an advanced therapeutic option for diabetes management, warranting further clinical exploration.

Abstract Background The purpose of the present study was to enhance the memory-boosting activity of the standardized hydroalcoholic Camellia sinensis extract (CSE) by the formation of nanophytosomes with Leciva S70 phospholipid. The central composite design was used to optimize the solvent evaporation method for the formulation of C. sinesis phytosomes (CSP). Results The optimized formulation had a mean particle size of 212.3 nm ± 0.39, PDI of 0.238 ± 0.0197, and zeta potential of −42.02 ± 0.995 mV. C. sinensis phytosome formation was confirmed by analytical techniques. The aqueous solubility of the developed CSP was 95.92 ± 0.31, which is 7.34 times greater than that of pure CSE (13.07 ± 0.19). CSP was found more effective than either pure CSE (26.42 ± 0.4654%) or the physical mixture (32.15 ± 0.4596%) in releasing the CSE from the formulation (72.16 ± 0.5248%). Acute toxicity study corroborated the safety of CSP in rats. CSP demonstrated a significant (p < 0.05) reduction in escape and transferred latency on both days (15th and 16th) as compared to CSE, indicating the improvement of the memory-boosting activity. Furthermore, CSP-treated rats significantly improved acetylcholine (Ach) levels and brain tissue concentration compared with CSE. Moreover, the phytosomal formulation of CSP exhibited its rationality with an improvement of bioavailability by 3.21 folds compared with pure CSE. Conclusion The presence of phospholipids in the CSP formulation and the formation of smaller particles may aid in crossing the blood–brain barrier, increasing brain tissue concentration and bioavailability. This, in turn, leads to an increase in memory-boosting activity. Graphical abstract

The objective of the present investigation was to development of enteric coated tablet of fenoprofen calcium. The study results showed that disintegration time and dissolution studies of inner core tablet found to be in the range of 7.15 to 13.34 min and 95.92±0.011% at 30 min. The press coat tablets at optimum concentrations of hydroxy propyl cellulose (200 mg) and ethyl cellulose N-22 (200 mg) showed the % drug release 83.53±0.014% at 12 h, % cumulative drug release of enteric coated tablet of optimized batch FT9 showed 76.08±0.045 at 12h, it indicated that drug release at sustained manner. The presence of EC in hydrophilic compression coat retarded the initial swelling of the coat in weakly acidic pH, but in alkaline pH, enhancement in drug release rate was observed due to the dissolution of EC from the coat with time resulting in a porous coat structure, resulted in a faster and controlled drug release in the target area. The present studies, it was concluded that an optimized formulation successfully delaying drug release for a programmable period of time to attain colon targeted delivery.

Purpose. The present study aimed to improve the aqueous solubility, permeability, bioavailability, and nootropic potential of standardized Emblica officinalis extract (EOE) by developing a novel phytosomal formulation. Method. Emblica officinalis extract-loaded phytosomes (EOPs) were prepared using solvent evaporation. The EOP was prepared at different molar ratios of extract and phospholipid. Herein, the effects of phospholipid extract ratio (A), temperature (B), and reaction time (C) were systematically investigated on entrapment efficiency using Box-Behnken design. In vitro and in vivo characterizations of the optimized formulation were performed. Results. Optimized EOP formulation (89.90 ± 0.24 μg/ml) exhibited improved aqueous solubility than plain EOE (11.85 ± 0.25 μg/ml). The optimized formulation’s particle size and Zeta potential were 198.4 ± 0.20 nm and −39.0 ± 0.40 mv. DSC and XRD studies confirmed the partial amorphization of EOE in phytosomes. Optimized formulation exhibited 69.82 ± 0.17% of EOE release at 12 h and followed zero-order release kinetics. Moreover, the phytosomal formulation of EOE exhibited its rationality with an improvement of bioavailability by 2.7 folds compared with pure EOE. Compared to EOE, EOP showed significantly (p<0.05 lower escape and transfer latencies on both days in MWMT and EPMT, indicating more effective memory-enhancing activity. Furthermore, EOP-treated rats exhibited improved acetylcholine (Ach) levels than EOE. Brain tissue concentrations measured following EOP oral administration (1.06 ± 0.04 μg/ml) were substantially greater (p<0.05) than those following EOE (0.32 ± 0.07 μg/ml). The brain dopamine and serotonin concentration were found to be higher (16.27 ± 1.209 and 43.28 ± 1.550 ng/ml) in the EOP-treated group as compared to the pure extract-treated group (10.40 ± 1.185 and 32.79 ± 1.738 ng/ml). Conclusion. Improvement of aqueous solubility, permeability, dissolution, bioavailability, and narrower particle size distribution could facilitate enhancement in the nootropic potential of EOE phytosomal formulation.

In the pursuit of effective diabetes management, inhibiting α-amylase activity stands as a critical strategy. This inhibition regulates post-meal blood sugar levels by retarding carbohydrate digestion, mitigating abrupt glucose spikes, and enhancing glycemic control, thus safeguarding against diabetic complications. In this study, molecular docking and DFT investigations were conducted on phytochemical compounds sourced from various plants, unveiling Conanine, Friedelin, Sennoside A, and Sennoside B as promising candidates. These compounds demonstrated robust binding affinities exceeding -9 kcal/mol when targeted against α-amylase, with Conanine leading the charge at -9.5 kcal/mol. Sennoside A and Sennoside B exhibited their effectiveness by forming multiple hydrogen bonds with the enzyme, underlining their strong binding interactions. Furthermore, DFT calculations affirmed the favorable chemical reactivity profiles of these ligands, characterized by significant HOMO-LUMO energy gaps. This research offers valuable insights into potential therapeutic agents for diabetes management, promising better glycemic control and a brighter future for individuals with diabetes.

Fungal histone deacetylases (HDACs) are enzymes known for their crucial role in gene expression regulation through histone deacetylation, leading to chromatin compaction and transcriptional control. Among them, Rpd3, a lysine deacetylase, has been extensively studied for its involvement in chromatin remodeling, gene expression, and various biological processes such as development, cell cycle progression, and stress response. Rpd3's significance in fungal pathogenesis makes it a potential target for antifungal therapies. This study utilized advanced computational tools to identify biogenic molecule hits against a homology-modeled Rpd3 structure. Molecular dynamics simulations verified the stability of the hits while docking studies revealed strong binding affinities (< – 8 kcal/mol) for Rpd3-ZINC000019941755, Rpd3-ZINC000005854718, and Rpd3-ZINC000014762752 complexes. The correlation between binding interactions and HOMO–LUMO properties was established through density functional theory calculations. Additionally, in silico pharmacokinetic and drug-likeness assessments highlighted the potential of these hits as drug candidates. Consequently, ZINC000019941755, ZINC000005854718, and ZINC000014762752 emerge as promising candidates for further investigation.

The main objective of this research was to evaluate the anticonvulsant activity of a series of newly synthesized oxadiazoles using spectroscopic, in vitro and in silico studies. The in-vivo anticonvulsant activity of the synthesized oxadiazole derivatives was evaluated through maximal electroshock seizure (MES) and subcutaneous pentylenetetrazol (scPtz) tests in mice. Spectroscopic techniques were employed to characterize the synthesized compounds. Drug-likeness prediction and in silico ADME assessment, molecular docking, molecular dynamics simulation, and density functional theory calculation were performed to explore the potential of synthesized compounds. The results of the in-vivo study revealed that compounds 6b, 6g, and 6h exhibited protection against PTZ-induced seizure in mice, indicating their potential as anticonvulsant agents. Drug-likeness prediction and In silico ADME assessment indicated that the synthesized compounds satisfied all the necessary requirements. Docking studies revealed that compound 6b exhibited the highest negative binding affinity against CaSRs, suggesting strong binding interactions. Stability of protein–ligand complex was confirmed using 100 ns molecular dynamics simulation. The calculated energies of frontier molecular orbitals using density functional theory indicated a good HOMO–LUMO gap for all the derivatives, further supporting their bioactivity. The newly synthesized oxadiazoles, especially compounds 6b, 6g, and 6h, demonstrated promising anticonvulsant activity in the in-vivo tests. The molecular docking study revealed potential interactions with CaSRs, particularly for compound 6b. Molecular dynamics simulations confirmed the conformational stability of the docked protein–ligand complexes over 100 ns. Overall, this research provides valuable insights into the potential of synthesized oxadiazoles as anticonvulsant agents, paving the way for further drug development studies.

The present work was proposed to chemically modified Pectin with its hydrophilicity reduced and potential for being an universal excipient. The Bulk densities of NTGT granules were found to be 0.3473 which indicate good packing capacity. Carr’s index of NTGT granules were found to be 5.88 which indicate excellent flow properties. Hausner ratio of NTGT granules were found to be 1.0621. Angle of repose of NTGT granules were excellent flow properties. The formulations MP1P2 after optimization to limit the release in the first 3 hrs could also be equally effective. Comparative evaluation of the designed formulations, the release of nateglinide from tablets coated with eudragit RL100 was progressively prolonged, as concentration of eudragit in the coating solution was increased about 63.91% at 12hr of NTGEUD3 batch. The formulated batches gives a clear indication that once daily formulations of nateglinide as oral hypoglycemics drug can be designed using this approach and subsequent release at a consistently uniform rate for sustained action has been achieved.

Sonchus asper also locally known as prickly sow-thistle, rough milk thistle, spiny sowthistle, spiny-leaved sow thistleordudhi, is a widespread plant an annual or biennial herb sometimes reaching a height of 200 cm. with spiny leaves and yellow flowers resembling those of the dandelion. Traditionally it has been used in the treatment of numerous disorders and many resembling plants of the genus Sonchas create confusion hence its standardization is necessary. In the present work we have tried to standardize the entire herb based on physical, chemical, microscopical, and Physico-chemical investigations to provide the proximate values for its proper identification. The present work will help the traditional healers for selecting the correct herb for treating different disorders and avoid the wrong choice of crude drugs which may lead to unsatisfactory results for intended use or it may cause discomfort for many patients. Further work is going on for the biological evaluation of this herb to provide scientific validation of its traditional claims.

Objective: An ICH-compliant RP-HPLC approach was created and validated in order to measure the concentrations of HCTZ and LIS in bulk and mixed medicinal dosage forms. This procedure was subsequently submitted for certification. Methods: Column, a Phenomenex Luna C18(2) (250 x 4.6 mm, 5μ) with a Methanol: Formic acid (30:70) mobile phase, a flow rate is kept as 01 mL/min, the wavelength of detection was 215 nm, and a used detector was PDA. Results: Hydrochlorothiazide (HCTZ)) and lisinopril (LIS) both had linear calibration curves (r2 = 0.9973 and 0.9983, respectively) for the ranges of concentration 4.0 to 6.0 and 10.0 to 15.0 μg/mL. The proposed technique eluted LIS in 3.97 minutes and hydrochlorothiazide in 4.53 minutes. Lisinopril had a recovery rate of 99.31 to 99.83%, whereas hydrochlorothiazide had a recovery rate of 100.75 to 101.16%. At 1.22 and 0.31 μg/mL, respectively, HCTZ as well as LIS had the lowest detectable values. It was found that the LoQs for lisinopril and hydrochlorothiazide were 0.97 and 3.75 μg/mL, respectively. Conclusion: It was found that the current RP-HPLC technique is reliable, simple to use, accurate, linear, efficient, and rapid. With a shorter analysis period, this method offers better resolution between the two compounds. Therefore, there is sufficient evidence to include the approach in regular lisinopril and hydrochlorothiazide analysis in a variety of pharmaceutical companies and academic institutions.

Scientific fraternity revealed the potential of stimuli-responsive nanotherapeutics for cancer treatment that aids in tackling the major restrictions of traditionally reported drug delivery systems. Among stimuli-responsive inorganic nanomaterials, metal-organic frameworks (MOFs) have transpired as unique porous materials displaying resilient structures and diverse applications in cancer theranostics. Mainly, it demonstrates tailorable porosity, versatile chemical configuration, tunable size and shape, and feasible surface functionalization, etc. The present review provides insights into the design of stimuli-responsive multifunctional MOFs for targeted drug delivery and bioimaging for effective cancer therapy. Initially, the concept of cancer, traditional cancer treatment, background of MOFs, and approaches for MOFs synthesis have been discussed. After this, applications of stimuli-responsive multifunctional MOFs-assisted nanostructures that include pH, light, ions, temperature, magnetic, redox, ATP, and others for targeted drug delivery and bioimaging in cancer have been thoroughly discussed. As an outcome, the designed multifunctional MOFs showed an alteration in properties due to the exogenous and endogenous stimuli that are beneficial for drug release and bioimaging. The several reported types of stimuli-responsive surface-modified MOFs revealed good biocompatibility to normal cells, promising drug loading capability, target-specific delivery of anticancer drugs into cancerous cells, etc. Despite substantial progress in this field, certain crucial issues need to be addressed to reap the clinical benefits of multifunctional MOFs. Specifically, the toxicological compatibility and biodegradability of the building blocks of MOFs demand a thorough evaluation. Moreover, the investigation of sustainable and greener synthesis methods is of the utmost importance. Also, the low flexibility, off-target accumulation, and compromised pharmacokinetic profile of stimuli-responsive MOFs have attracted keen attention. In conclusion, the surface-modified nanosized design of inorganic diverse stimuli-sensitive MOFs demonstrated great potential for targeted drug delivery and bioimaging in different kinds of cancers. In the future, the preference for stimuli-triggered MOFs will open a new frontier for cancer theranostic applications.

This study aimed to develop a straightforward, sensitive, exact, quick, and accurate reverse phase high performance liquid chromatography (RP-HPLC) method for figuring out how much lisinopril is in pharmaceutical gels and other large amounts of medication. Agilent Zorbax Bonus-RP column (250 x 4.6 mm, 5μ) was used for the chromatographic separation. “A mobile phase composed of methanol and trifluoroacetic acid (50:50 v/v) was used to develop the analytical procedure. The flow was found to be occurring at a rate of 1-mL/min and with a wavelength of 215 nm. The retention time was 2.28 min. In a concentration range from 3–7 μg/mL (r2=0.998), the drug’s response was determined to be linear. The LoQ was 1.11 μg/mL, while the LoD was 0.36 μg/mL. Lisinopril’s %assay was determined to be 98.22%, while assays for the other medicines in the commercial formulation showed no interference from the excipients. This method functions well and can be applied to routine analysis.

Andrographis paniculata is a promising extract that has gained attention due to its broad range of pharmacological effects. It is now being researched extensively as a natural hepatoprotective surrogate with potential efficacy against alcohol-induced hepatotoxicity. However, it has several flaws that restrict its therapeutic value, including less bioavailability due to inadequate lipophilic solubility and indigent gastrointestinal absorption. This study highlights the development of self-assembled phytosome nanocarriers to improve lipophilic solubility and bioavailability. In this study, nanophytosomes of Andrographis paniculata extract (APE) were engineered to improve the rate of drug release and hepatoprotective efficiency of the extract. The nanophytosomes of Andrographis paniculata (APP) were formulated utilizing a full factorial design technique, which took into account a variety of variables that could lead to an optimized formulation. Particle size analysis, zeta potential, differential scanning calorimetry (DSC), Fourier transformation infrared spectroscopy (FTIR), powder X-ray diffractometer (PXRD), proton nuclear magnetic resonance (1H NMR), scanning electron microscopy (SEM), and solubility studies were used for physicochemical characterization. The decrease in the crystalline nature of nanophytosome was shown by PXRD and SEM. The production of the phyto-phospholipid complex was verified with the help of 1H NMR, DSC, and FTIR. The dissolution rate in nanophytosomes was also observed to be increased and sustained. Furthermore, in pharmacodynamics assessment, APP was found more effective as compared to APE. Overall, the findings of this study revealed that nanophytosome formulation might be used as promising drug delivery for sustained drug release and improved hepatoprotection efficacy.

Mannich bases and thiosemicarbazide individually show varied pharmacological activities like anticancer, antimicrobial, antifungal, anticonvulsant, antimalarial, analgesic and anti-inflammatory. By using mutual prodrug concept, first mannich bases were synthesized using aldehyde, ketones and secondary amines with aliphatic, aromatic, cyclic and heterocyclic nature using mannich reaction and then condensed with thiosemicarbazide to form mannich bases of thiosemicarbazide as mutual prodrug. Structural characterization of synthesized compounds was done using IR and H-NMR. Complexicity in the structure of reactants lead to change in reaction time, temperature and % yield of final product. The compounds were screened for anti- microbial activity using Escherichia Coli (8739) Staphylococcus aureus (25923), anti-fungal activity using Aspergillus niger (16404), Candida albicans (10231) using BHI (brain heart infusion) broth dilution method and anti tubercular activity by micro plate Alamar Blue assay (MABA).

Objective: Present study aimed to develop and validate a novel, unique, simple, quick, cost-effective, sensitive, specific, accurate, precise, rugged, and robust bioanalytical method for the quantification of gallic acid in rat plasma by reverse phase high-performance liquid chromatography (RP-HPLC) using gradient elution technique. Methods: The stationary phase was a Zorbax SB C18 5 µ (4.6*150) mm column, with the mobile phase being water with 0.1 percent formic acid (A): acetonitrile (ACN) with 0.08 percent formic acid (B). Gradient chromatographic method was used throughout this experiment from the point of view of the estimation of gallic acid from herbal formulations when present along with other phytoconstituents. So at the gradient method, all the present phytoconstituents has cleared off from the column and no any strongly adsorption of phytoconstituents occurred. The experiment was carried out at a flow rate of 1.0 ml/min at 30 °C utilising PDA detectors at 271 nm. The proposed method was validated for different parameters. Results: The approach was found to be linear in the concentration range of 0.5-100 µg/ml, with a r2 of 0.9998. There was not observed any interference of co-eluting peaks of endogenous compounds from the biological matrix at the same retention time (Rt) of gallic acid. The RSD (%) of intra and interday precision was found to be within acceptable limit. The overall % mean recovery was found to be 99.97%. LOD and LOQ were found to be 0.1 and 0.5 μg/ml, respectively. In terms of fluctuation in essential parameters and operating settings, the devised bioanalytical approach was shown to be rugged and resilient. Short-term, long-term, autosampler, bench-top, and freeze-thaw stability experiments revealed that gallic acid is stable. Conclusion: The developed method described in this report was found to be well within an acceptable range. Hence, in the future, this method can be used successfully for the estimation of gallic acid alone or in combination with another analyte or marker present in bulk or an extract containing various phytoconstituents in pharmacokinetic, bioequivalence, and therapeutic drug monitoring studies in clinical laboratories.

The cases of bacterial multidrug resistance are increasing every year and becoming a serious concern for human health. Multidrug efflux pumps are key players in the formation of antibiotic resistance, which transfer out a broad spectrum of drugs from the cell and convey resistance to the host. Efflux pumps have significantly reduced the efficacy of the previously available antibiotic armory, thereby increasing the frequency of therapeutic failures. In gram-negative bacteria, the AcrAB-TolC efflux pump is the principal transporter of the substrate and plays a major role in the formation of antibiotic resistance. In the current work, advanced computer-aided drug discovery approaches were utilized to find hit molecules from the library of biogenic chalcones against the bacterial AcrB efflux pump. The results of the performed computational studies via molecular docking, drug-likeness prediction, pharmacokinetic profiling, pharmacophore mapping, density functional theory, and molecular dynamics simulation study provided ZINC000004695648, ZINC000014762506, ZINC000014762510, ZINC000095099506, and ZINC000085510993 as stable hit molecules against the AcrB efflux pumps. Identified hits could successfully act against AcrB efflux pumps after optimization as lead molecules.Communicated by Ramaswamy H. Sarma

Lisinopril belongs to BCS class III having high solubility and low permeability.Reportedly, the oral bioavailability of lisinopril is 25 to 30% and its effectiveness is limited due to poor permeability.Hence, the current investigation is aimed to formulate transdermal ion-pair gel using a permeation enhancer for enhanced delivery of lisinopril across the stratum corneum and evaluate pharmacokinetics of lisinopril in rabbits.The formation of ion-pair is corroborated using Fourier Transform Infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), X-ray Diffraction (XRD), zeta potential, particle size analysis, oil/water partition coefficient study, etc. Optimization of the formulation was done using 3 2 factorial designs.Total nine batches (F1-F9) were prepared and the effect of propylene glycol (mL; X1) and carbopol 934 (%; X2) was investigated on gel viscosity (Y1) and permeability through rabbit's skin at 8h (Y2).Propylene glycol exhibited a non-significant (p>0.05)effect on both gel viscosity and skin permeability whereas carbopol 934 demonstrated significant (p<0.05)positive and negative effects on both, respectively.The viscosity of all the lisinopril ion-pair gel (F1-F9) was ranging between 17.24 ± 2.16 Pa.s (Batch F9) to 7.54 ± 1.34 Pa.s (Batch F4).Ex-vivo permeability of all the prepared batches (F1-F9) across excised rabbit's skin was ranging between 85.93 ± 1.26% (Batch F4) to 62.17 ± 1.57% (Batch F9).Remarkably, optimized formulation (F4) exhibited 1.7 folds improvement in skin permeability and 2.4 folds improvement in bioavailability than plain lisinopril gel.These findings demonstrate that ion pair formation is a promising strategy for significantly improving the skin permeability of lisinopril.