Discovery of thiazolidinedione-based pancreatic lipase inhibitors as anti-obesity agents: synthesis, in silico studies and pharmacological investigations.

A series of new 2,5-disubstituted arylidene derivatives of thiazolidinedione (16a-e, 17a-d, 18a-c) designed using molecular hybridization approach were synthesized, structurally characterized, and explored for their anti-obesity potential via inhibition of Pancreatic Lipase (PL). Compound 18a presented the most potent PL inhibitory activity with IC50 = 2.71 ± 0.31 µM, as compared to the standard drug, Orlistat (IC50 = 0.99 µM). Kinetic study revealed reversible competitive mode of enzyme inhibition by compound 18a with an inhibitory constant value of 1.19 µM. The most promising compound 18a revealed satisfactory binding mode within the active site of the target protein (human PL, PDB ID: 1LPB). Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analysis were performed for the most promising compound 18a, which showed potent inhibition according to the results of in vitro studies. Furthermore, a stable conformation of the 1LPB-ligand suggested the stability of this compound in the dynamic environment. The ADME and toxicity analysis of the compounds were examined using web-based online platforms. Results of in vivo studies confirmed the anti-obesity efficacy of compound 18a, wherein oral treatment with compound 18a (30 mg/kg) resulted in a significant reduction in the body weight, BMI, Lee index, feed intake (in Kcal), body fat depots and serum triglycerides. Compound 18a significantly decreased the levels of serum total cholesterol (TC) to 128.6 ± 0.59 mg/dl and serum total triglycerides (TG) to 95.73 ± 0.67 mg/dl as compared to the HFD control group. The present study identified disubstituted TZD derivatives as a new promising class of anti-obesity agents.Communicated by Ramaswamy H. Sarma.

Pancreatic lipase and its related proteins: where are we now?

Obesity is a disease of epidemic proportions, with a worrisome upward trend. The high consumption of lipids, a major energy source, leads to obesity because of their high calorific value. Pancreatic lipase (PTL), produced by pancreatic acinar cells, hydrolyzes 50-70% of triacylglycerol (TAG) from food. PTL-related protein 1 (PLRP1) and 2 (PLRP2) are also produced by these cells. In vertebrates, PLRP1 has relatively less lipolytic activity, whereas PLRP2 has an essential role in lipid digestion, especially in infants. In this review, we summarize the structure and function of PTL, PLRP1, and PLRP2, and the metabolic fate of PTL inhibitors. We also discuss the current status of clinical trials on orlistat and its combinations for obesity treatment.

Long-term antitrypanosomal effect of quinapyramine sulphate-loaded oil-based nanosuspension in T. evansi-infected mouse model.

The goal of the present work consisted of the formulation development and evaluation of quinapyramine sulphate (QS)-loaded long-acting oil-based nanosuspension for improved antitrypanosomal effect. QS was transformed into a hydrophobic ionic complex using anionic sodium cholate (Na.C). The complex was characterized by FTIR, DSC, and XRD. Oil-based nanosuspension was prepared by dispersing the QS-Na.C complex in thixotropically thickened olive oil. The nanoformulation was found to be cytocompatible (82.5 ± 5.87% cell viability at the minimum effective concentration [MEC]) in THP-1 cell lines and selectively trypanotoxic (p < 0.0001). The pharmacokinetic studies of QS-Na.C complex-loaded oily nanosuspension showed 13.54-fold, 7.09-fold, 1.78-fold, and 17.35-fold increases in t1/2, AUC0-∞, Vz/F, and MRT0-ꝏ, respectively, as compared to free QS. Moreover, a 7.08-fold reduction in plasma clearance was observed after the treatment with the optimized formulation in Wistar rats. Furthermore, treatment with QS-Na.C complex-loaded oily nanosuspension (7.5 mg/kg) in T. evansi-infected mice model showed the absence of parasitaemia for more than 75 days after the treatment during in vivo efficacy studies. The efficacy of the treatment was assessed by observation of blood smear and PCR assay for DNA amplification. To conclude, our findings suggest that the efficient delivery of QS from the developed QS-Na.C complex-loaded oily nanosuspension could be a promising treatment option for veterinary infections against trypanosomiasis.

Synthesis, molecular modelling and pharmacological evaluation of novel indole-thiazolidinedione based hybrid analogues as potential pancreatic lipase inhibitors.

A series of novel indole-thiazolidinedione hybrid analogues (7a to 7 u) were synthesised, characterised and evaluated for their potential Pancreatic Lipase (PL) inhibition. Amongst the screened analogues, 7r was found to be the most active PL inhibitor with an IC50 of 2.67 µM. Furthermore, enzyme inhibition kinetics study revealed a competitive mode of inhibition by the analogues. This fact was confirmed via fluorescence spectroscopy which further suggested the presence of one binding site for the synthesized analogues. Molecular docking was performed using human PL (PDB ID: 1LPB) and were in agreement with the in vitro results (Pearson's r = 0.8355, p < 0.05). A molecular dynamics study (100 ns) indicated that 7r was stable in a dynamic environment. The analogue 7r exhibited potential antioxidant activity and was devoid of cytotoxic effect on RAW 264.7 cells. Based on the in-vitro profiles, 7r was selected for the in-vivo pharmacological evaluation. Oral triglyceride tolerance test highlighted effect of 7r on the inhibition of triglyceride absorption. A four-week treatment of 7r in the HFD feed mice provided information regarding its anti-obesity effect with respect to parameters such as body weight, triglycerides, total cholesterol and high-density lipids. Quantification of the faecal triglyceride contents inveterates the potential role of 7r in the PL inhibition. Overall, the synthesized analogue 7r exerted an anti-obesity effect comparable to orlistat. All these results demonstrated the potential role of the newly synthesised indole-thiazolidinedione hybrid analogues in PL inhibition and may be studied further to find potential drug candidates for treating obesity.Communicated by Ramaswamy H. Sarma.

Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide-Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors.

Inhibition of Pancreatic lipase (PL) is considered to be a promising target for the management of obesity, owing to its crucial role in the digestion of dietary triglycerides. A series of 31 indolyl ketohydrazide-hydrazone analogs (5 aa-cm) were designed, synthesized and evaluated for their PL inhibitory potential. The analogs were designed using molecular modelling studies. The designed analogs were then synthesized by condensation of indolyl oxoacetohydrazide with various substituted benzaldehydes. All the synthesized analogs showed PL inhibitory activity in the range of 4.13-48.35 µM, as compared with orlistat (0.86±0.09 µM). The most potent analog 5 bi (IC50 =4.13±0.95 µM) was found to show a competitive type of inhibition with Ki value of 0.725 µM. Additionally, the molecular docking study proved the binding of analog 5 bi at the active site of PL (PDB ID: 1LPB) with MolDock score of -141.279 kcal/mol. It also exhibited various interactions with the key amino acids namely Phe77, Phe215, Tyr114, Ser152, Arg256, His263, etc. Furthermore, the protein-ligand complex of analog 5 bi was found to be stable in molecular dynamics simulation for 100 ns with RMSD of less than 3.2 and 4 Šfor the protein and ligand, respectively. The current work hereby provides a basis for the potential role of indolyl ketohydrazide-hydrazone analogs in PL inhibition and further optimization could result in the generation of new leads as anti-obesity agents.

SET7, a lysine-specific methyl transferase: An intriguing epigenetic target to combat diabetic nephropathy.

Diabetic nephropathy (DN) is a dreadful complication of diabetes that affects ∼50% of diabetics and is a leading cause of end-stage renal disease (ESRD). Studies have linked aberrant expression of lysine methyltransferases (KMTs) to the onset and progression of DN. SET7 is a KMT that methylates specific lysine residues of the histone and nonhistone proteins. It plays an important role in the transforming growth factor-ß (TGF-ß)-induced upregulation of extracellular matrix (ECM)-associated genes that are responsible for the inflammatory cascade observed in DN. Inhibiting SET7 has potential to attenuate renal disorders in animal studies. This review will focus on the role of SET7 in DN and its potential as a therapeutic target to combat DN.

Chromone Containing Hybrid Analogs: Synthesis and Applications in Medicinal Chemistry.

The use of privileged scaffolds has proven beneficial for generating novel bioactive scaffolds in drug discovery program. Chromone is one such privileged scaffold that has been exploited for designing pharmacologically active analogs. The molecular hybridization technique combines the pharmacophoric features of two or more bioactive compounds to avail a better pharmacological activity in the resultant hybrid analogs. The current review summarizes the rationale and techniques involved in developing hybrid analogs of chromone, which show potential in fields of obesity, diabetes, cancer, Alzheimer's disease and microbial infections. Here the molecular hybrids of chromone with various pharmacologically active analogs or fragments (donepezil, tacrine, pyrimidines, azoles, furanchalcones, hydrazones, quinolines, etc.) are discussed with their structure-activity relationship against above-mentioned diseases. Detailed methodologies for the synthesis of corresponding hybrid analogs have also been described, with suitable synthetic schemes. The current review will shed light on various strategies utilized for the design of hybrid analogs in the field of drug discovery. The importance of hybrid analogs in various disease conditions is also illustrated.

Topical Nanotherapeutics for Treating MRSA-Associated Skin and Soft Tissue Infection (SSTIs).

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) imposes a major challenge for the treatment of infectious diseases with existing antibiotics. MRSA associated with superficial skin and soft tissue infections (SSTIs) is one of them, affecting the skin's superficial layers, and it includes impetigo, folliculitis, cellulitis, furuncles, abscesses, surgical site infections, etc. The efficient care of superficial SSTIs caused by MRSA necessitates local administration of antibiotics, because oral antibiotics does not produce the required concentration at the local site. The topical administration of nanocarriers has been emerging in the area of drug delivery due to its advantages over conventional topical formulation. It enhances the solubility and permeation of the antibiotics into deeper layer of the skin. Apart from this, antibiotic resistance is something that needs to be combated on multiple fronts, and antibiotics encapsulated in nanocarriers help to do so by increasing the therapeutic efficacy in a number of different ways. The current review provides an overview of the resistance mechanism in S. aureus as well as various nanocarriers reported for the effective management of MRSA-associated superficial SSTIs.

PCB-77 biodegradation potential of biosurfactant producing bacterial isolates recovered from contaminated soil.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants widely distributed in the environment and possess deleterious health effects. The main objective of the study was to obtain bacterial isolates from PCB-contaminated soil for enhanced biodegradation of PCB-77. Selective enrichment resulted in the isolation of 33 strains of PCB-contaminated soil nearby Bhilai steel plant, Chhattisgarh, India. Based on the prominent growth using biphenyl as the sole carbon source and the confirmation of its degradation by GC-MS/MS analysis, four isolates were selected for further study. The isolates identified by 16S rRNA gene sequencing were Pseudomonas aeruginosa MAPB-2, Pseudomonas plecoglossicida MAPB-6, Brucella anthropi MAPB-9, and Priestia megaterium MAPB-27. The isolate MAPB-9 showed a degradation of 66.15% biphenyl, while MAPB-2, MAPB-6, and MAPB-27 showed a degradation of 62.06, 57.02, and 56.55%, respectively in 48 h. Additionally, the degradation ability of these strains was enhanced with addition of co-metabolite glucose (0.2%) in the culture medium. Addition of glucose showed 100% degradation of biphenyl by MAPB-9, in 48 h, while MAPB-6, MAPB-2, and MAPB-27 showed 97.1, 67.5, and 53.3% degradation, respectively as analyzed by GC-MS/MS. Furthermore, in the presence of inducer, PCB-77 was found to be 59.89, 30.49, 27.19, and 4.43% degraded by MAPB-6, MAPB-9, MAPB-2, and MAPB-27, respectively in 7 d. The production of biosurfactants that aid in biodegradation process were observed in all the isolates. This was confirmed by ATR-FTIR analysis that showed the presence of major functional groups (CH2, CH3, CH, = CH2, C-O-C, C-O) of the biosurfactant. The biosurfactants were further identified by HPTLC and GC-MS/MS analysis. Present study is the first to report PCB-77 degradation potential of Pseudomonas aeruginosa, B. anthropi, Pseudomonas plecoglossicida, and Priestia megaterium. Similarly, this is the first report on Pseudomonas plecoglossicida and Priestia megaterium for PCB biodegradation. Our results suggest that the above isolates can be used for the biodegradation of biphenyl and PCB-77 in PCB-contaminated soil.

Metagenomic analysis for taxonomic and functional potential of Polyaromatic hydrocarbons (PAHs) and Polychlorinated biphenyl (PCB) degrading bacterial communities in steel industrial soil.

Iron and steel industries are the major contributors to persistent organic pollutants (POPs). The microbial community present at such sites has the potential to remediate these contaminants. The present study highlights the metabolic potential of the resident bacterial community of PAHs and PCB contaminated soil nearby Bhilai steel plant, Chhattisgarh (India). The GC-MS/MS analysis of soil samples MGB-2 (sludge) and MGB-3 (dry soil) resulted in identification of different classes of POPs including PAHs {benzo[a]anthracene (nd; 17.69%), fluorene (15.89%, nd), pyrene (nd; 18.7%), benzo(b)fluoranthene (3.03%, nd), benzo(k)fluoranthene (11.29%; nd), perylene (5.23%; nd)} and PCBs (PCB-15, PCB-95, and PCB-136). Whole-genome metagenomic analysis by Oxford Nanopore GridION Technology revealed predominance of domain bacteria (97.4%; 97.5%) followed by eukaryote (1.4%; 1.5%), archaea (1.2%; 0.9%) and virus (0.02%; 0.04%) in MGB-2 and MGB-3 respectively. Proteobacteria (44.3%; 50.0%) to be the prominent phylum followed by Actinobacteria (22.1%; 19.5%) in MBG-2 and MBG-3, respectively. However, Eukaryota microbial communities showed a predominance of phylum Ascomycota (20.5%; 23.6%), Streptophyta (18.5%, 17.0%) and unclassified (derived from Eukaryota) (12.1%; 12.2%) in MGB-2 and MGB-3. The sample MGB-3 was richer in macronutrients (C, N, P), supporting high microbial diversity than MGB-2. The presence of reads for biphenyl degradation, dioxin degradation, PAH degradation pathways can be further correlated with the presence of PCB and PAH as detected in the MGB-2 and MGB-3 samples. Further, taxonomic vis-à-vis functional analysis identified Burkholderia, Bradyrhizobium, Mycobacterium, and Rhodopseudomonas as the keystone degrader of PAH and PCB. Overall, our results revealed the importance of metagenomic and physicochemical analysis of the contaminated site, which improves the understanding of metabolic potential and adaptation of bacteria growing under POP contaminated environments.

Mechanistically acting anti-obesity compositions/formulations of natural origin: a patent review (2010-2021).

INTRODUCTION: Current health trends indicate that the rate of incidence of obesity has risen considerably. According to the World Health Organization (WHO) report 2017, the issue of obesity has grown to an epidemic proportion, with over 4 million people dying every year. Orlistat, a potent pancreatic lipase (PL) inhibitor for long-term treatment of obesity has been recently reported to cause hepatic and renal toxicities. Hence, there is a need to develop newer, safer and efficacious therapeutics that targets obesity and its associated disorders. AREAS COVERED: The present article attempts to review patents on compositions of natural origin that include either combination of two or more lead NPs/whole extract(s)/ mixture of one or more NPs/extracts from various plants and micro-organisms. Patents that were granted during the period 2010 to 2021 have been considered. EXPERT OPINION: The article highlights the recent trends in the rise of the global obesity population. Patents are classified based on the mechanism of action of extracts/NPs. It has been observed that in the years 2013, 2017 and 2019 maximum number of patents from China, South Korea, United States and Japan have been filed for the anti-obesity compositions.

Synthesis, molecular modelling, in vitro and in vivo evaluation of conophylline inspired novel benzyloxy substituted indole glyoxylamides as potent pancreatic lipase inhibitors.

Pancreatic lipase is a digestive enzyme involved in the hydrolysis of dietary fats. Orlistat, a potent pancreatic lipase inhibitor, is widely prescribed for long-term obesity treatment. Nevertheless, orlistat is reported for severe adverse effects including hepatotoxicity and pancreatitis. In the present study, a novel series of 11 benzyloxy substituted indole glyoxylamides were designed, synthesized and evaluated for in vitro pancreatic lipase inhibitory activity. Three analogues, 10b, 11b and 11c, exhibited potent activity (IC50 ≤ 2.5 µM), with 11b exhibiting a potent IC50 of 1.68 µM comparable to orlistat (IC50 = 0.99 µM). Further, 11b exhibited reversible competitive inhibition with an inhibitory constant value of 0.98 µM. Molecular docking of these analogues was in agreement with in vitro results, wherein the MolDock scores exhibited significant correlation with their inhibitory activity (Pearson's r = 0.7122). A 50 ns molecular dynamics simulation of 11b-pancreatic lipase complex confirmed the role of extended alkyl interactions along with π-π stacking and π-cation interactions, in stabilizing the ligand (Maximum RMSD ≈ 3 Å) in the active site. Gastro-intestinal absorption and toxicity prediction of the three potent analogues highlighted the suitability of 11b for in vivo experiments. 11b at a dose of 20 mg/kg exhibited anti-obesity efficacy comparable to orlistat (10 mg/kg), wherein the serum triglycerides were found to be 94.95 and 83.85 mg/dL, respectively. Further, faecal triglyceride quantification indicated 11b to act through pancreatic lipase inhibition similar to orlistat. The present study identified a novel pancreatic lipase inhibitory benzyloxy substituted bis(indolyl) glyoxylamide 11b, with promising anti-obesity activity.Communicated by Ramaswamy H. Sarma.

Design, synthesis and biological evaluation of N-substituted indole-thiazolidinedione analogues as potential pancreatic lipase inhibitors.

Pancreatic Lipase (PL) is a key enzyme responsible for the digestion of 50%-70% of dietary triglycerides, hence its inhibition is considered as a viable approach for the management of obesity. A series of indole-TZD hybrid analogues were synthesized, characterized and evaluated for their PL inhibitory activity. Knoevenagel condensation of various substituted indole-3-carboxaldehyde with substituted thiazolidinediones resulted in the formation of titled analogues. Analogues 6d and 6e exerted potent PL inhibitory activity (IC50 -6.19 and 8.96 µM, respectively). Further, these analogues exerted a competitive mode of PL inhibition. Moreover, molecular modelling studies were in agreement with the in vitro results (Pearson's r = .8682, p < .05). The fluorescence spectroscopic analysis further supported the strong binding affinity of these analogues with PL. A molecular dynamics study (20 ns) indicated that these analogues were stable in a dynamic environment. Thus, the present study highlighted the potential role of indole-thiazolidinedione hybrid analogues as potential PL inhibitors and further optimization might result in the development of new PL inhibitory lead candidates.

U.S. FDA Approved Drugs from 2015-June 2020: A Perspective.

In the present work, we report compilation and analysis of 245 drugs, including small and macromolecules approved by the U.S. FDA from 2015 until June 2020. Nearly 29% of the drugs were approved for the treatment of various types of cancers. Other major therapeutic areas of focus were infectious diseases (14%); neurological conditions (12%); and genetic, metabolic, and cardiovascular disorders (7-8% each). Itemization of the approved drugs according to the year of approval, sponsor, target, chemical class, major drug-metabolizing enzyme(s), route of administration/elimination, and drug-drug interaction liability (perpetrator or/and victim) is presented and discussed. An effort has been made to analyze the pharmacophores to identify the structural (e.g., aromatic, heterocycle, and aliphatic), elemental (e.g., boron, sulfur, fluorine, phosphorus, and deuterium), and functional group (e.g., nitro drugs) diversity among the approved drugs. Further, descriptor-based chemical space analysis of FDA approved drugs and several strategies utilized for optimizing metabolism leading to their discoveries have been emphasized. Finally, an analysis of drug-likeness for the approved drugs is presented.

Preparation and Evaluation of Quinapyramine Sulphate-Docusate Sodium Ionic Complex Loaded Lipidic Nanoparticles and Its Scale Up Using Geometric Similarity Principle.

The objective of the present work is to prepare and evaluate ionically complexed Quinapyramine sulphate (QS) loaded lipid nanoparticles and its scale up using geometric similarity principle. Docusate sodium (DS), at a molar ratio of 1:2 of QS to DS, was used to prepare hydrophobic Quinapyramine sulphate-Docusate sodium (QS-DS) ionic complex. Based on the difference in total solubility parameter and polarity of QS-DS complex and different lipids, precirol was selected as a lipid for the preparation of lipidic nanoparticles. The particle size, zeta potential, and % entrapment efficiency (%EE) of QS-DS ionic complex loaded solid lipid nanoparticles (QS-DS-SLN) was found to be 250.10 ± 26.04 nm, -27.41 ± 4.18 mV and 81.26 ± 4.67% respectively. FTIR studies confirmed the formation of QS-DS ionic complex. DSC and XRD studies revealed the amorphous nature of QS in QS-DS-SLN. The spherical shape of nanoparticles was confirmed by scanning electron microscopy. QS-DS-SLN showed sustained release of QS for up to 60 h. No significant difference was observed in particle size, zeta potential, and % entrapment efficiency of pilot-scale batch prepared by using rotational speed of 700 rpm. In conclusion, ionic complexation approach can be used to increase % EE of charged drugs into lipid nanoparticles.

Development and validation of a new HPTLC-HRMS method for the quantification of a potent pancreatic lipase inhibitory lead Echitamine from Alstonia scholaris.

Alstonia scholaris is an important indole alkaloid rich medicinal plant with diverse pharmacological activity. To understand the effect of extraction techniques, the stem bark sample of A. scholaris was subjected to continuous hot percolation, ultrasonic extraction, and cold maceration techniques. Continuous hot percolation technique extractive exhibited a potential pancreatic lipase (PL) inhibitory activity and further bio-assay guided fractionation resulted in the isolation of echitamine with a PL inhibitory activity (IC50 = 10.92 µM). A new validated HPTLC-HRMS method was developed for the quantification of echitamine by using a mobile phase of chloroform: methanol (80:20, v/v) with 0.04% formic acid. Echitamine content in the individual extractives were in direct correlation with the PL inhibitory activity (Pearson's r = -0.9409). The molecular docking studies further confirmed the PL inhibitory potential of echitamine. These results clearly highlight the role of echitamine as a natural product-based lead for potent PL inhibitory activity.

Evaluation of biphenyl- and polychlorinated-biphenyl (PCB) degrading Rhodococcus sp. MAPN-1 on growth of Morus alba by pot study.

This study focused on isolation of bacteria with biphenyl/polychlorinated biphenyl (PCB) degrading ability from the rhizosphere of Morus alba (mulberry plant). Repetitive enrichment of rhizospheric soil samples with biphenyl resulted in the isolation of Rhodococcus sp. MAPN-1, identified by 16S rRNA gene sequence analysis. The bacterium showed growth on five different aromatic compounds (naphthalene, salicylic acid, benzoic acid, dibenzofuran and anthracene). Benzoic acid was detected as the major metabolite during biphenyl degradation using high-performance thin-layer chromatography (HPTLC) with Rf 0.42 at 254 nm. Further GC-MS/MS study showed 95% and 15% degradation of biphenyl and dichlorobiphenyl, respectively. A pot study was conducted to evaluate the effect of presence of biphenyl on M. alba and the role of biphenyl degrader Rhodococcus sp. MAPN-1 in relation to phytoremediation. Morus alba twigs in biphenyl spiked soil (100 mg/kg and 300 mg/kg) inoculated with Rhodococcus sp. MAPN-1 showed growth, whereas, growth of plants (control) was adversely affected in biphenyl-spiked uninoculated soil. It is the first report of isolation of Rhodococcus sp. MAPN-1 from the rhizosphere of Morus alba, its capability to degrade biphenyl, thereby showing a positive effect on the plant growth grown in biphenyl spiked soil.

Impact of quercetin on pharmacokinetics of quetiapine: insights from in-vivo studies in wistar rats.

Quercetin (QCN) is commonly used in high doses as a dietary supplement for weight loss. Psychotic patients are at greater risk of developing obesity than the general population. The present study was designed to understand the impact of QCN on the exposure of quetiapine (QTE), an anti-psychotic drug with narrow therapeutic index and brain penetrating capability. The content of QTE in rat plasma was analyzed through liquid chromatography-tandem mass spectrometry. The results showed a significant (p < 0.05) increase in exposure of QTE (peroral dosed) in the animals pre-treated with QCN as compared to the control group. All the animals pre-treated with QCN, succumbed to death within 3-5 min of intravenous dosing of QTE (1 mg/kg). The studies in rat liver S9 fraction indicated that QCN could increase the metabolic stability of QTE by inhibiting the activity of CYP enzymes. The brain to plasma ratio of QTE increased upon QCN pre-treatment (2.6 vs 7.7), which could be attributed to P-glycoprotein inhibition at the blood-brain barrier by QCN. The current set of studies indicated that serious herb-drug interaction between QCN and QTE might occur when they are co-administered. Caution is advised for concomitant use of QCN rich dietary supplements with QTE.

Design, synthesis, evaluation, and molecular modeling studies of indolyl oxoacetamides as potential pancreatic lipase inhibitors.

A series of indolyl oxoacetamide analogs was synthesized, characterized, and evaluated for their pancreatic lipase inhibitory activity using porcine pancreatic lipase (type II) and 4-nitrophenyl butyrate. Compound 8d exhibited a potent inhibition, with an IC50 value of 4.53 µM, followed by 8c (IC50 = 5.12 µM), compared with the standard drug, orlistat (IC50 = 0.99 µM). Furthermore, analogs 8c and 8d exhibited a reversible competitive inhibition, similar to orlistat. Molecular docking studies of the compounds 7a-f and 8a-f were in agreement with the in vitro results, wherein 8d exhibited a potential MolDock score of -163.052 kcal/mol. A 10-ns molecular dynamics simulation of 8d complexed with pancreatic lipase confirmed the role of π-π stacking and π-cation interactions with the lid domain and Arg 256, respectively, in stabilizing the ligand at the active site (maximum observed root mean square deviation ≈ 2 Å). The present study led to the identification of novel indolyl oxoacetamides (8a-d) as potential pancreatic lipase inhibitory leads that might further result in enhanced potency through lead optimization.

Rapid and cost-effective LC-MS/MS method for determination of hydroxycitric acid in plasma: Application in the determination of pharmacokinetics in commercial Garcinia preparations.

Garcinia cambogia is one of the most commonly used anti-obesity dietary supplements, and hydroxycitric acid (HCA) is a major constituent in the commercial preparations of Garcinia. High doses of HCA are often consumed without much awareness of its pharmacokinetic and toxicokinetic parameters, and therefore, a complete understanding of its effects is lacking. The first step in understanding these parameters is the availability of a reliable bioanalytical method. Here, we present the first report on a UPLC-MS/MS method for analysis of HCA in rat plasma after a simplified and cost-effective protein precipitation. Chromatographic separation of the analytes in the supernatant was achieved using hydrophilic interaction liquid chromatography, where mass parameters were optimized and a rapid 5-min quantitative assay was developed. The method was highly sensitive, accurate, precise and linear in the concentration range of 10.5-5000 ng/mL (validated according to the United States Food and Drug Administration guidelines). Further, the method was successfully used to describe the pharmacokinetic profile of HCA in rat plasma after the administration of pure HCA and commercial Garcinia preparations.