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Twenty-two monomers and dimers of artemisinin having chalcone as a linker were synthesised, and their antimalarial activity against Plasmodium falciparum was determined, and a quantitative structure-activity relationship (QSAR) was developed. Artemisinin is a frontline antimalarial drug known worldwide but is threatened because of the rapidly emerging artemisinin-resistant strain Plasmodium falciparum. In vitro , antimalarial IC 50 (half-maximal inhibitory concentration) activity of a molecule against malaria parasites provides a good first screen for identifying the antimalarial potential of a particular molecule. The most active compound was artemisinin dimer dimethoxy chalcone as a linker (22) with IC 50 of 4.34 nM. The molecular mechanism was explored through in silico docking & ADMET studies for the active compounds.

Eugenol( 1 ), a terpenoid found in Ocimum, has various biological activities. The present study aims at extraction, isolation of the plant secondary metabolite eugenol ( 1 ), it's derivatisation and structure identification as bioactive molecules. Synthesis and antiplasmodial activity ( in-vitro and in-vivo ), of a series of fourteen novel eugenol-based 1,2,3-triazole derivatives was done in the present study. Derivatives 5a - 5n showed good antimalarial activity against the strain Plasmodium falciparum NF 54 . Derivative 5 m , IC 50 at 2.85 µM was found to be several times better than its precursor 1 (106.82 µM) whereas the derivative 5n showed three fold better activity than compound 1 , in vitro . The structure-activity relationship of the synthesised compounds indicated that the presence of triazole ring in eugenol analogues is responsible for their good activity. Compound 5m , was further evaluated for in-vivo antimalarial activity which showed about 79% parasitemia suppression. It is the first report on antimalarial activity of triazole eugenol derivatives.

As a part of novel discovery of drugs from natural resources, present study was undertaken to explore the antibacterial potential of chalcone Indl-2 in combination with different group of antibiotics. MIC of antibiotics was reduced up to eight folds against the different cultures of E. coli by both chalcones. Among the two compounds, the i. e. 1-(3', 4,'5'-trimethoxyphenyl)-3-(3-Indyl)-prop-2-enone (6, Indl-2), a chalcone derivative of gallic acid (Indl-2) was better along with tetracycline (TET) worked synergistically and was found to inhibit efflux transporters as obvious by ethidium bromide efflux confirmed by ATPase assays and docking studies. In combination, Indl-2 kills the MDREC-KG4 cells, post-antibiotic effect (PAE) of TET was prolonged and mutant prevention concentration (MPC) of TET was also decreased. In-vivo studies revealed that Indl-2 reduces the concentration of TNF-α. In acute oral toxicity study, Indl-2 was non-toxic and well tolerated up-to dose of 2000 mg/kg. Perhaps, the study is going to report gallic acid derived chalcone as synergistic agent acting via inhibiting the primary efflux pumps., (© 2024 Wiley‐VHCA AG, Zurich, Switzerland.)

Background: Malaria remains one of the major health concerns, especially in tropical countries. Although drugs such as artemisinin-based combinations are efficient for treating Plasmodium falciparum, the growing threat from multi-drug resistance has become a major challenge. Thus, there is a constant need to identify and validate new combinations to sustain current disease control strategies to overcome the challenge of drug resistance in the malaria parasites. To meet this demand, liquiritigenin (LTG) has been found to positively interact in combination with the existing clinically used drug chloroquine (CQ), which has become unfunctional due to acquired drug resistance., Purpose: To evaluate the best interaction between LTG and CQ against CQ- resistant strain of P. falciparum. Furthermore, the in vivo antimalarial efficacy and possible mechanism of action of the best combination was also assessed., Methods: The in vitro anti-plasmodial potential of LTG against CQ- resistant strain K1 of P. falciparum was tested using Giemsa staining method. The behaviour of the combinations was evaluated using the fix ratio method and evaluated the interaction of LTG and CQ by calculating the fractional inhibitory concentration index (FICI). Oral toxicity study was carried out in a mice model. In vivo antimalarial efficacy of LTG alone and in combination with CQ was evaluated using a four-day suppression test in a mouse model. The effect of LTG on CQ accumulation was measured using HPLC and the rate of alkalinization of the digestive vacuole. Cytosolic Ca 2+ level, mitochondrial membrane potential, caspase-like activity, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and Annexin V Apoptosis assay to assess anti-plasmodial potential. Proteomics analysis was evaluated by LC-MS/MS analysis., Results: LTG possesses anti-plasmodial activity on its own and it showed to be an adjuvant of CQ. In in vitro studies, LTG showed synergy with CQ only in the ratio (CQ: LTG-1:4) against CQ-resistant strain (K1) of P. falciparum. Interestingly, in vivo studies, LTG in combination with CQ showed higher chemo-suppression and enhanced mean survival time at much lower concentrations compared to individual doses of LTG and CQ against CQ- resistant strain (N67) of Plasmodium yoelli nigeriensis. LTG was found to increase the CQ accumulation into digestive vacuole, reducing the rate of alkalinization, in turn increasing cytosolic Ca 2+ level, loss of mitochondrial potential, caspase-3 activity, DNA damage and externalization of phosphatidylserine of the membrane (in vitro). These observations indicate the involvement of apoptosis-like death of P. falciparum that might be due to the accumulation of CQ., Conclusion: LTG showed synergy with CQ in the ratio LTG: CQ, 4:1) in vitro and was able to curtail the IC 50  of CQ and LTG. Interestingly, in vivo in combination with CQ, LTG showed higher chemo-suppression as well as enhanced mean survival time at a much lower concentrations of both the partners as compared to an individual dose of CQ and LTG. Thus, synergistic drug combination offers the possibility to enhance CQ efficacy in chemotherapy., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper., (Copyright © 2023. Published by Elsevier GmbH.)

Researchers are exploring natural resources in search of a new and effective anti-malarial compound to address the challenges in malarial treatment due to emerging incidences of drug-resistant strains. Following background knowledge of traditional medicine, we evaluated the in-vitro and in-vivo anti-malarial efficacy of Putranjiva P. roxburghii (Putranjivaceae) twigs ethanol extracts and fraction (PRT). In-vitro parasite-specific lactate dehydrogenase (pLDH) assay was performed using a chloroquine-sensitive Plasmodium falciparum strain. The results of the in-vitro study were further validated by in-vivo anti-malarial studies on P. berghei Keyberg 173 (K173) infected mice. The crude ethanol extract of the PRT showed the most moderate antiparasitic activity (IC 50  = 15.51 μg/mL). In contrast, its butanol fraction extract showed potent activity (IC 50  = 5.14 μg/mL) with a selectivity index (SI) of 28.87. Two phytochemicals, viz. 2, 4 dihydroxy-5-(hydroxymethyl) benzoic acid (DHMBA), and quebrachitol (QBC), were identified with anti-parasitic activity (IC 50  = 5.01 μg/mL and 0.87 μg/mL) and selectivity index (SI) of 45 and 158. The in-vivo studies confirmed the significant anti-malarial activity of QBC at the dose of 30 and 60 mg/kg body weight with chemo-suppression values of 73.26% and 61.88%, respectively. The present study demonstrates the bioactive marker-based standardization of P. roxburghii twig, the antiplasmodial potential of PRT, and the role of QBC in suppressing parasitemia. The findings of the study support QBC as a prospective lead for a natural product-based adjunct remedy to conventional antiparasitic agents for malarial infectious., Competing Interests: Declaration of Competing Interest We confirm that no known conflicts of interest are associated with the current publication., (Copyright © 2022. Published by Elsevier B.V.)

The mosquito repellent Nepetalactone rich Nepeta cataria L. (catmint) plant has a variety of therapeutic and industrial potential. Reports on the genetic diversity of N. cataria germplasm are minimal globally and need attention for adding a new variety into commercial cultivation. The present study, therefore, assessed the genetic diversity among thirteen half-sib genotypes of N. cataria using agro economic and phytochemical traits. The experimental set has shown substantial variation for agro economic traits studied. Among all the studied populations, fresh herb-based essential oil content ranged from 0.1 % to 0.3 %, with a grand mean of 1.67 %. However, the estimated oil yield ranged from 44.4 kg/h to 120.73 kg/h with an average of 71.34 kg/h. Among the eleven phytochemical constituents detected in different concentrations in the essential oil of experimental sets, 4aα,7α,7aα-Nepetalactone (67.9-87.5 %) constituted the significant proportion of essential oil. Altogether, based on mean comparison, the population NC8 was found to be promising for estimated oil yield and 4aα,7α,7aα-Nepetalactone content. The greater heritability estimates (h 2 bs) and genetic advance as percent of mean (GAM) were observed for important economic parameters, i. e., oil content, herb yield, and oil yield. The cluster analysis revealed the least interactions between various agro economic and phytochemical variables. The microscopic study of trichome showed a positive correlation of abaxial leaf surface with essential oil content. The promising antimicrobial potential of catmint oil was also observed against human health-related pathogens. The results infer from our study provide valuable insight for genetic improvement and product development in the catmint germplasm., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Vitamin B12 deficiency is prevalent among individuals globally. Inadequate consumption of B12 rich diet and low bioavailability (due to diet based/physiological factors) are linked to the deficiency of Vitamin B12 inside the body. Bioavailability enhancers augment the bioavailability of an ingested substance (drug/nutrient) thus increasing their concentration inside the body and maximizing their therapeutic benefits. In traditional medicine, Licorice ( Glycyrrhiza glabra ) finds utility in the treatment of various health conditions. Thus, the present study aimed to examine the potential of ethanolic extract obtained from G. glabra roots to enhance the bioavailability of Vitamin B12. The effect of ethanolic extract of G. glabra (GgEtOH) on intestinal absorption enhancement of B12 was assessed in vitro on Caco-2 and ex-vivo everted gut sac models. The influence of extract on the pharmacokinetics of Vitamin B12 was determined in vivo in Swiss albino mice. GgEtOH significantly enhanced the permeation (Papp) of B12 by 2-5 fold in vitro (25, 50, and 100 μg/ml concentrations) and ex-vivo (250 and 500 μg/ml concentrations). The pharmacokinetic parameters of B12 such as Cmax, AUC, Tmax, etc. were also significantly elevated in vivo upon oral administration of B12 (1 mg/kg dose) in combination with GgEtOH (100 and 1,000 mg/kg dose). These preliminary findings indicate that the ethanolic extract of G. glabra is capable of enhancing the bioavailability of Vitamin B12. To the best of our knowledge, this is the first report to demonstrate herbal extract-mediated enhancement of Vitamin B12 bioavailability through in vitro, ex vivo , and in vivo assays., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sharma, Pathak, Tyagi, Khan, Shanker, Darokar and Pal.)

Glabridin (Glb), a polyphenolic flavonoid inhibits the growth of MDRSA (Multidrug resistant S. aureus) 4627 by inducing ROS. Glb in combination with Norfloxacin (Nor) synergistically induced oxidative stress. Increased ROS/RNS levels, in particular, affected macromolecules' (DNA, lipid, protein) integrity and distorted cell morphology. We found correlation between drug-effects and up-/down-regulation of oxidative stress-related as well as MDR genes. These findings could considerably potentiate the dosing routine of Nor in combination with Glb, which holds a promising prospective as a antibacterial agent against S. aureus.

Malaria eradication is still a major global health problem in developing countries, which has been of more concern ever since the malaria parasite has developed resistance against frontline antimalarial drugs. Historical evidence proves that the plants possess a major resource for the development of novel anti-malarial drugs. In the present study, the bioactivity guided fractionation of the oleogum-resin of Boswellia serrata Roxb. yielded the optimum activity in the ethyl acetate fraction with an IC 50 of 22 ± 3.9 μg/mL and 26.5 ± 4.5 μg/mL against chloroquine sensitive (NF54) and resistant (K1) strains of Plasmodium falciparum respectively. Further, upon fractionation, the ethyl acetate fraction yielded four major compounds, of which 3-Hydroxy-11-keto-β-boswellic acid (KBA) was found to be the most potent with IC 50 values 4.5 ± 0.60 µg/mL and 6.25 ± 1.02 μg/mL against sensitive and resistant strains respectively. KBA was found to inhibit heme detoxification pathways, one of the most common therapeutic targets, which probably lead to an increase in reactive oxygen species (ROS) and nitric oxide (NO) detrimental to P. falciparum. Further, the induced intracellular oxidative stress affected the macromolecules in terms of DNA damage, increased lipid peroxidation, protein carbonylation as well as loss of mitochondrial membrane potential. However, it did not exhibit any cytotoxic effect in VERO cells. Under in vivo conditions, KBA exhibited a significant reduction in parasitemia, retarding the development of anaemia, resulting in an enhancement of the mean survival time in Plasmodium yoelii nigeriensis (chloroquine-resistant) infected mice. Further, KBA did not exhibit any abnormality in serum biochemistry of animals that underwent acute oral toxicity studies at 2000 mg/kg body weight., (Copyright © 2021. Published by Elsevier Masson SAS.)

Cliv-92 is a mixture of three structurally similar coumarinolignoids and a proven hepatoprotective agent. Low aqueous solubility and poor bioavailability are notable hindrances for its further use. Therefore, glycyrrhetinic acid-linked chitosan nanoparticles loaded with Cliv-92 were prepared for active targeting to the liver. The nanoparticles were prepared by the ionic gelation method to avoid the use of toxic solvents/rigorous agitation. The method of preparation was optimized using a central composite design with independent variables, namely polymer: drug ratio (3:1, w/w), crosslinker concentration (0.5%), and stirring speed (750 rpm). The optimized nanoparticles had a mean particle size of 185.17 nm, a polydispersity index of 0.41, a zeta potential of 30.93 mV, and a drug loading of 16.30%. The prepared formulation showed sustained release of approximately 63% of loaded Cliv-92 over 72 h. The nanoparticles were freeze-dried for long-term storage and further characterized. The formulation was found to be biocompatible for parenteral delivery. In vivo imaging study showed that optimized nanoparticles were preferentially accumulated in the liver and successfully targeting the liver. The present study successfully demonstrated the improved pharmacokinetic properties (≈12% relative bioavailability) and efficacy profile (evidenced by in vivo and histopathological studies) of fabricated Cliv-92 nanoparticles., (© 2021. American Association of Pharmaceutical Scientists.)

We explored the antibacterial potential (alone and combination) against multidrug resistant (MDR) Pseudomonas aeruginosa isolates KG-P2 using synthesized thieno[3,2-c]pyran-2-ones in combination with different antibiotics. Out of 14 compounds, two compounds (3g and 3l) abridged the MIC of tetracycline (TET) by 16 folds. Compounds was killing the KG-P2 cells, in time dependent manner, lengthened post-antibiotic effect (PAE) of TET and found decreased the mutant prevention concentration (MPC) of TET. In ethidium bromide efflux experiment, two compounds repressed the drug transporter (efflux pumps) which is further supported by molecular docking of these compounds with efflux complex MexAB-OprM. In another study, these compounds inhibited the synthesis of biofilm., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Twenty one chalcone derivatives were synthesized using Claisen-Schmidt condensation, their antimalarial activity against Plasmodium falciparum was determined and quantitative structure-activity relationship (QSAR) was developed. Condensation of substituted acetophenones with various aromatic aldehydes at room temperature gave chalcones in 75-96% yield. Chalcones are secondary metabolites of terrestrial plants, precursors for the biosynthesis of flavonoids and exhibit various biological activities. Antiplasmodial IC 50 (half-maximal inhibitory concentration) activity of a compound against malaria parasites in vitro provides a good first screen for identifying the antimalarial potential of the compound. The most active compound was Trans-3-(1H-indol-3-yl)-1-(2'-hydroxyphenyl)-2-propen-1-one (1b) with IC 50 of 2.1 µM/L. Molecular mechanism was explored through in silico docking & ADMET studies for the active compounds.

4-chloro eugenol (4CE), a semisynthetic analog of phytomolecule eugenol exhibited potent antiplasmodial activity with IC 50 in the range of 1.5-5 μM against sensitive as well as drug resistant strain of P. falciparum. This analog also showed synergy with a clinically used antimalarial drug artesunate and was able to curtail the IC 50 of artesunate up to 4-5 folds. Although, 4CE did not show any effect on heme polymerization, the most common drug target in the malaria parasite, it could increase the level of reactive oxygen species (ROS) and reactive nitrogen species (RNS) alone as well as in combination with artesunate. Further, 4CE induced oxidative stress was observed to affect the macromolecules in terms of DNA damage, protein carbonylation and lipid peroxidation. At the physiological level, cellular organelles like mitochondria and endoplasmic reticulum were observed to be get affected by 4CE in terms of membrane depolarization and calcium ion leakage respectively. These observations could be validated by expression analysis of oxidative stress responsive genes and proteins. Further, in in vivo assay, 4CE showed significant chemo-suppression of parasitemia as well as an increase in mean survival time in the murine malaria model. Interestingly, in combination with artesunate, 4CE showed higher chemo-suppression as well as enhanced mean survival time at a much lower concentrations of both the partners as compared to an individual dose of artesunate and 4CE. A combination of 4CE and artesunate was also observed to attenuate cerebral malaria pathogenesis., (Copyright © 2021 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Putranjivah (Putranjiva roxburghii Wall, family - Putranjivaceae) is an Indian native medicinal plant used to treat many diseases such as treatment of mouth and stomach ulcers, hot swellings, smallpox, burning sensation and ophthalmopathy. The study of chemical constituents in the bark of P. roxburghii resulted in a new triterpene ( 6 ) along with five known triterpenoids ( 1 - 5 ). The chemical characterisation was based on 1 H, 13 C, 2D-NMR experimentation, and ESI-MS data. The anti-plasmodial activity was investigated by measuring parasite-specific lactate dehydrogenase (pLDH) based in vitro assay. The IC 50 value results showed that friedlein (2.40 ± 0.70) and roxburghonol (4.10 ± 1.7 μg/ml) possess better anti-plasmodial activity than other isolated triterpenes ( 2 - 5 ) but not as potent as chloroquine (0.023 ± 0.002 μg/ml) against chloroquine-sensitive Plasmodium falciparum (3D7) strain.

Malaria remains one of the major health concerns due to the resistance of Plasmodium species toward the existing drugs warranting an urgent need for new antimalarials. Thymol derivatives were known to exhibit enhanced antimicrobial activities; however, no reports were found against Plasmodium spp. In the present study, the antiplasmodial activity of thymol derivatives was evaluated against chloroquine-sensitive (NF-54) and -resistant (K1) strains of Plasmodium falciparum . Among the thymol derivatives tested, 4-chlorothymol showed potential activity against sensitive and resistant strains of P. falciparum . 4-Chlorothymol was found to increase the reactive oxygen species and reactive nitrogen species level. Furthermore, 4-chlorothymol could perturb the redox balance by modulating the enzyme activity of GST and GR. 4-Chlorothymol also showed synergy with chloroquine against chloroquine-resistant P. falciparum . 4-Chlorothymol was found to significantly suppress the parasitemia and increase the mean survival time in in vivo assays. Interestingly, in in vivo assay, 4-chlorothymol in combination with chloroquine showed higher chemosuppression as well as enhanced mean survival time at a much lower concentration as compared to individual doses of chloroquine and 4-chlorothymol. These observations clearly indicate the potential use of 4-chlorothymol as an antimalarial agent, which may also be effective in combination with the existing antiplasmodial drugs against chloroquine-resistant P. falciparum infection. In vitro cytotoxicity/hemolytic assay evidently suggests that 4-chlorothymol is safe for further exploration of its therapeutic properties., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kumar, Mina, Kumar, Pal, Ahmad, Tandon and Darokar.)

Introduction: Endophyte is considered a source of natural bioactive secondary metabolites that provides an array of bioactive lead compounds. The present study was aimed to determine the antimicrobial and anti-inflammatory potential of fungal endophytes isolated from Catharanthus roseus., Methods: A total of seven fungal endophytes crude extract were screened against bacterial pathogens. Of these, Curvularia geniculata CATDLF7 crude extract exhibited the most potent inhibitory activity against bacterial pathogens. Hence, CATDLF7 crude extract was subjected to chromatographic separation. This purification leads to the isolation of six pure compounds (1PS - 6PS). Of these, 3PS was found to be a major constituent and most effective against clinical isolates of methicillin- resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration (MIC) values ranging from 100 to 200 μg/ml. Based on the spectroscopic data, 3PS was characterized as α,β- dehydrocurvularin. This compound also showed synergistic interaction with norfloxacin and reduced its MIC up to 32-folds with a fractional inhibitory concentration index (FICI) of 0.09., Results: To understand the possible antibacterial mechanism of action, α,β-dehydrocurvularin alone (100 μg/ml) exhibited efflux pump inhibitory potential by 0.84 fold decreasing in ethidium bromide (EtBr) fluorescence. In addition, α,β-dehydrocurvularin inhibited inflammatory cytokines TNF-α and IL-6 production, which is further validated by molecular docking scores -4.921 and -5.641, respectively, for understanding orientation and binding affinity., Conclusion: Overall, the results highlighted identifying bioactive compound α,β-dehydrocurvularin, which could be used as an antimicrobial and anti-inflammatory agent., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Liver cancer is ranked as the fifth most prevalent and third most lethal cancer worldwide. The incidence rates of this cancer are on the rise, and only limited treatment options are available., Methods: To identify and optimize the inhibitors of liver cancer cell-lines, a QSAR model was developed by using multiple linear regression methods. The robustness of the model was validated through statistical methods and wet-lab experiments., Results: The developed QSAR models yielded high activity descriptor relationship accuracy of 91%, referred to by regression coefficient (r 2 = 0.91), and a high activity prediction accuracy of 89%. The external predicted (pred_r 2 ) ability of the model was found to be 90%., Conclusion: The QSAR study indicates that chemical descriptors such as to measure of electronegative atom count (Epsilon3), atom type count descriptors (MMFF_10), number of a carbon atom connected with four single bonds (SssssCE- index), molecular weight and, number of oxygen atom connected with two aromatic bonds (SaaOE-index) are significantly correlated with anticancer activity. The model, which was validated statistically and through wet-lab experiments, was further used in the virtual screening of potential inhibitors against the liver cancer cell line WRL68. ADMET risk screening, synthetic accessibility, and Lipinski's rule of five are used to filter false positive hits. AfterwardS, to achieve a set of aligned ligand poses and rank the predicted active compounds, docking studies were carried out. The studied compounds and their metabolites were also analyzed for different pharmacokinetics parameters. Finally, a series of compounds was proposed as anticancer agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Being crucial part of plant-based novel discovery of drug from natural resources, a study was done to explore the antibacterial potential of curcumin mimics in combination with antibiotics against multidrug resistant isolates of Pseudomonas aeruginosa. The best candidate Van D, a curcumin mimics reduced the MIC of tetracycline (TET) up to 16 folds against multidrug resistant clinical isolates. VanD further inhibited the efflux pumps as evident by ethidium bromide efflux and by in-silico docking studies. In another experiment, it was also found that Van D inhibits biofilm synthesis. This derivative kills the KG-P2, an isolate of P. aeruginosa in a time dependent manner, the post-antibiotic effect (PAE) of tetracycline was extended as well as mutant prevention concentration (MPC) of TET was also decreased. In Swiss albino mice, Van D reduced the proinflammatory cytokines concentration. In acute oral toxicity study, this derivative was well tolerated and found to be safe up to 1000 mg/kg dose. To the best of our knowledge, this is the first report on curcumin mimics as synergistic agent via inhibition of efflux pump., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Staphylococcus aureus is an opportunistic bacterium of the human body and a leading cause of nosocomial infections. Methicillin resistant S. aureus (MRSA) infections involving biofilm lead to higher mortality and morbidity in patients. Biofilm causes serious clinical issues, as it mitigates entry of antimicrobials to reach the etiological agents. It plays an important role in resilient chronic infections which place an unnecessary burden on antibiotics and the associated costs. To combat drug-resistant infection involving biofilm, there is a need to discover potential anti-biofilm agents. In this study, activity of polyphenolic flavonoid glabridin against biofilm formation of methicillin resistant clinical isolates of S. aureus is being reported for the first time. Crystal violet assay and scanning electron microscopy evidences shows that glabridin prevents formation of cells clusters and attachment of methicillin resistant clinical isolate (MRSA 4423) of S. aureus to the surface in a dose dependent manner. Gel free proteomic analysis of biofilm matrix by LC-ESI-QTOF confirmed the existence of several proteins known to be involved in cells adhesion. Furthermore, expression analysis of cell surface proteins revealed that glabridin significantly down regulates an abundance of several surface-associated adhesins including fibronectin binding proteins (FnbA, FnbB), serine-aspartate repeat-containing protein D (SdrD), immunoglobulin-binding protein G (Sbi), and other virulence factors which were induced by extracellular glucose in MRSA 4423. In addition, several moonlighting proteins (proteins with multiple functions) such as translation elongation factors (EF-Tu, EF-G), chaperone protein (DnaK), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and pyruvate kinase (PK) were detected on the cell surface wherein their abundance was inversely proportional to surface-associated adhesins. This study clearly suggests that glabridin prevents biofilm formation in S. aureus through modulation of the cell surface proteins., (Copyright © 2020 Gangwar, Kumar and Darokar.)

A polyphenolic flavonoid, Silymarin isolated from Silybum marianum is widely known for its hepatoprotective action. In the present study anti-plasmodial activity of Silymarin has been demonstrated for the first time having IC 50 of 14 ± 0.33 μM against the NF-54 strain of P. falciparum with high selectivity index (>100). The parasitostatic action is exerted through inhibition of β-hematin/hemozoin formation which is due to the interaction ( Kd  = 3.63 ± 0.9µM) of silymarin with free heme in a Stoichiometry of 1:1 Silymarin: heme complex resulting into heme-induced membrane damage in the parasite. Silymarin could hinder the glutathione and hydrogen peroxide-induced heme detoxification. Silymarin also induces apoptosis in the parasite through the elevation of caspase-3 level in a dose-dependent manner. Results from the docking studies suggest that Silymarin interacts with heme.

Pyrazinamide (PZA), a crucial component of anti-TB therapy, is a prodrug. PZA interacts with PncA protein to be converted into its functional form i.e. pyrazinoic acid (POA). It has unique feature to kill dormant tubercle bacilli of acidic environment. Although significance of pH environment in PZA activation has been investigated in several of previous studies, insight into the significant atomistic variations in the interaction pattern of PZA with PncA, at different pH environments, are still required to be explored. On the other hand, continuously emerging PncA mutants, associated with PZA resistance, have also become a serious threat for global TB control program. Therefore, the current study was designed to understand the role of pH environment in the PZA activation and to explore the PZA resistance mechanism in various PncA mutants. The study included various in silico experiments like molecular docking, MD simulation, binding free energy estimation, PCA and FEL. In our study, we have found pH-3 and pH-5 environment as a highly significant environment for PZA activation. It was found that protonation or deprotonation of PZA activation site (PAS) residues, majorly K48, D56, K96 and E107, resulted in rearrangement of the PAS according to the pH conditions. It has also been observed that positioning of PZA binding near to Fe 2+ and residues of catalytic triad (i.e. D8, K96 and C138) also play a very crucial role in the activation of PZA. The overall insight from the current study may help to develop new therapeutics against PncA mutated PZA resistance.Communicated by Ramaswamy H. Sarma.

Multidrug-resistant Staphylococcus aureus infections place a huge burden on the healthcare sector and the wider community. An increasing rate of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has necessitated the development of alternative agents. We previously reported that usnic acid (UA) has activity against MRSA; here, we report the effect of UA in combination with norfloxacin on the drug resistance of MRSA clinical isolates. We observed that the combination of UA-norfloxacin significantly reduces the bacterial burden in mouse models infected with S. aureus, without causing any detectable associated toxicity. Proteomic analysis indicated that UA-norfloxacin induces oxidative stress within cells, which leads to membrane damage and inhibits metabolic activity and biosynthesis of peptidoglycan and fatty acids. Collectively, this study provides evidence that UA in combination with norfloxacin may be a potential candidate for development into a resistance-modifying agent for the treatment of invasive MRSA infections., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Use of harmful chemicals and expensive maintenance of cold-storage conditions for controlling sprouting are among the major problems in potato storage. Here, 20 essential oils (EOs) were tested for their sprouting-inhibiting and sprouting-inducing activities. Overall, treatments of lemon grass (LG) and clove (CL) oils could induce sprouting whereas palmarosa (PR) and ajwain (AZ) oils could inhibit sprouting of potato tubers at normal-room-temperature (25 ± 2 °C) storage. Selected-EOs treatments affected sprouting by modulation of accumulation of reducing sugars, ethylene, and expression of genes involved in tuber-sprouting such as ARF, ARP, AIP and ERF. Surprisingly, 7-days AZ-treatments could inhibit sprouting for 30-days which was mediated via damaging apical meristem. However, LG- and CL-treated tubers could produce enhanced potato yield as well. Present work clearly demonstrates that selected-EOs can be used as a promising eco-friendly approach for inducing/inhibiting sprouting of potato tubers during potato storage and those enhancing sprouting can be used for enhancing productivity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The emergence of multi drug resistance (MDR) in Gram-negative bacteria (GNB) and lack of novel classes of antibacterial agents have raised an immediate need to identify antibacterial agents, which can reverse the phenomenon of MDR. The purpose of present study was to evaluate synergy potential and understanding the drug resistance reversal mechanism of chanoclavine isolated from Ipomoea muricata against the multi-drug-resistant clinical isolate of Escherichia coli (MDREC). Although chanoclavine did not show antibacterial activity of its own, but in combination, it could reduce the minimum inhibitory concentration (MIC) of tetracycline (TET) up to 16-folds. Chanoclavine was found to inhibit the efflux pumps which seem to be ATPase-dependent. In real-time expression analysis, chanoclavine showed down-regulation of different efflux pump genes and decreased the mutation prevention concentration of tetracycline. Further, in silico docking studies revealed significant binding affinity of chanoclavine with different proteins known to be involved in drug resistance. In in silico ADME/toxicity studies, chanoclavine was found safe with good intestinal absorption, aqueous solubility, medium blood-brain barrier (BBB), no CYP 2D6 inhibition, no hepatotoxicity, no skin irritancy, and non-mutagenic indicating towards drug likeliness of this molecule. Based on these observations, it is hypothesized that chanoclavine might be inhibiting the efflux of tetracycline from MDREC and thus enabling the more availability of tetracycline inside the cell for its action.

Background: Due to the limited availability of antibiotics, Gram-negative bacteria (GNB) acquire different levels of drug resistance. It raised an urgent need to identify such agents, which can reverse the phenomenon of drug resistance., Objective: To understand the mechanism of drug resistance reversal of glycosides; niaziridin and niazirin isolated from the pods of Moringa oleifera and ouabain (control) against the clinical isolates of multidrug-resistant Escherichia coli., Methods: The MICs were determined following the CLSI guidelines for broth micro-dilution. In-vitro combination studies were performed by broth checkerboard method followed by Time-Kill studies, the efflux pump inhibition assay, ATPase inhibitory activity, mutation prevention concentration and in-silico studies., Results: The results showed that both glycosides did not possess antibacterial activity of their own, but in combination, they reduced the MIC of tetracycline up to 16 folds. Both were found to inhibit efflux pumps, but niaziridin was the best. In real time expression pattern analysis, niaziridin was also found responsible for the down expression of the two important efflux pump acrB & yojI genes alone as well as in combination. Niaziridin was also able to over express the porin forming genes (ompA & ompX). These glycosides decreased the mutation prevention concentration of tetracycline., Conclusion: This is the first ever report on glycosides, niazirin and niaziridin acting as drug resistance reversal agent through efflux pump inhibition and modulation of expression pattern drug resistant genes. This study may be helpful in preparing an effective antibacterial combination against the drug-resistant GNB from a widely growing Moringa oleifera., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Multidrug resistance (MDR) put an alarming situation like preantibiotic era which compels us to invigorate the basic science of anti-infective chemotherapy. Hence, the drug resistant genes/proteins were explored as promising drug targets. Keeping this thing in mind, proteome of Pseudomonas aeruginosa PA01 was explored, which resulted in the identification of tripartite protein complexes (MexA, MexB, and OprM) as promising drug target for the screening of natural and synthetic inhibitors. The purpose of present investigation was to explore the drug resistance reversal potential mechanism of catharanthine isolated from the leaves of Catharanthus roseous. Hence, the test compound catharanthine was in silico screened using docking studies against the above receptors, which showed significant binding affinity with these receptors. In order to validate the in silico findings, in vitro evaluation of the test compound was also carried out. In combination, catharanthine reduced the minimum inhibitory concentration MIC of tetracycline (TET) and streptomycin up to 16 and 8 folds, respectively. Further, in time kill assay, catharanthine in combination with TET reduced the cell viability in concentration dependent manner and was also able to reduce the mutation prevention concentration of TET. It was also deduced that drug resistance reversal potential of catharanthine was due to inhibition of the efflux pumps.

In traditional, herbal medicine, and aromatherapy, use of essential oils and their aroma compounds have been known since long, for the management of various human diseases. The essential oil is a mixture of highly complex, naturally occurring volatile aroma compounds synthesized by medicinal and aromatic plants as secondary metabolites. Essential oils widely used in pharmaceutical, cosmetic, sanitary, food industry and agriculture for their antibacterial, antiviral, antifungal, antiparasitic, insecticidal, anticancer, neuroprotective, psychophysiological, and anti-aging activities. Moreover, volatile aroma compounds comprise a chemically diverse class of low molecular weight organic compounds with significant vapor pressure. However, aroma compounds produced by plants, mainly attract pollinators, seed dispersers and provide defense against pests or pathogens. However, in humans, about 300 active olfactory receptor genes are involved to detect thousands of different aroma compounds and modulates expression of different metabolic genes regulating human psychophysiological activity, brain function, pharmacological signaling, and therapeutic potential. Keeping in mind this importance, present database, namely, AromaDb (http://bioinfo.cimap.res.in/aromadb/) covers information of plant varieties/chemotypes, essential oils, chemical constituents, GC-MS profile, yield variations due to agro-morphological parameters, trade data, aroma compounds, fragrance type, and bioactivity details. The database includes 1,321 aroma chemical structures, bioactivities of essential oil/aroma compounds, 357 fragrance type, 166 commercially used plants, and their high yielding 148 varieties/chemotypes. Also includes calculated cheminformatics properties related to identification, physico-chemical properties, pharmacokinetics, toxicological, and ecological information. Also comprises interacted human genes affecting various diseases related cell signaling pathways correlating the use of aromatherapy. This database could be a useful resource to the plant's growers/producers, an aroma/fragrance industrialist, health professionals, and researchers exploring the potential of essential oils and aroma compounds in the development of novel formulations against human diseases.

Malaria the parasitic disease of tropical countries is seeking newer therapeutic strategies owing to the drug resistance to existing drugs. The pathogenesis after infection renders the host to oxidative stress resulting in an altered immune status. Natural products rich in phenols are a source of bio-actives that could have a role in alleviating such condition. The present study reports the phenol rich ethyl acetate extract from the petals of Rosa damascena (RdEa) to be active against Plasmodium falciparum in-vitro and Plasmodium berghei in-vivo. It restores the haemoglobin level while increasing the mean survival time and chemo-suppression in P. berghei infected mice. The HPLC characterised RdEa was found to be rich in Gallic acid and Rutin besides other phenols. RdEa was capable of scavenging the free radicals and modulating the pro-inflammatory mediators (IL6, TNF, IFN and NO) favourably and also restored the architecture of hepatocytes as evidenced through histopathology. The extract was able to arrest the lipopolysaccharide (LPS) induced damage of J774A.1 cells (murine macrophages) and was found to be safe in mice upto 2000 mg/kg body weight., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Zingiber montanum (J.Koenig) Link ex A.Dietr. (Zingiberaceae), commonly known as cassumunar-ginger, is a folk remedy for the treatment of inflammations, sprains, rheumatism and asthma. The aim of the present study was to assess the chemical composition, and antibacterial, antifungal, allelopathic and acetylcholinesterase inhibitory activities of the essential oil of Z. montanum originating from India., Results: The hydrodistilled essential oil of Z. montanum rhizome was analyzed using gas chromatography-flame ionization detection and gas chromatography-mass spectrometry. A total of 49 constituents, forming 98.7-99.9% of the total oil compositions, was identified. The essential oil was characterized by higher amount of monoterpene hydrocarbons (32.6-43.5%), phenylbutanoids (27.5-41.2%) and oxygenated monoterpenes (11.4-34.1%). Major constituents of the oil were sabinene (13.5-38.0%), (E)-1-(3',4'-dimethoxyphenyl)buta-1,3-diene (DMPBD) (20.6-35.3%), terpinen-4-ol (9.0-31.3%), γ-terpinene (1.1-4.8%) and β-phellandrene (1.0-4.4%). The oil was evaluated against eight pathogenic bacteria and two fungal strains. It exhibited low to good antibacterial activity (minimum inhibitory concentration: 125-500 µg mL -1 ) and moderate antifungal activity (250 µg mL -1 ) against the tested strains. The oil reduced germination (69.8%) and inhibited the root and shoot growth of lettuce significantly (LD 50 : 3.58 µL plate -1 ). However, it did not demonstrate acetylcholinesterase inhibitory activity up to a concentration of 10 mg mL -1 ., Conclusions: The essential oil of Z. montanum can be used as a potential source of DMPBD, terpinen-4-ol and sabinene for pharmaceutical products. The results of the present study add significant information to the pharmacological activity of Z. montanum native to India. © 2017 Society of Chemical Industry., (© 2017 Society of Chemical Industry.)

Background: Lawsonia inermis L. is a well-documented plant for cosmetic as well as medicinal properties. It is used by local communities in India and Nigeria for the treatment of many parasitic diseases, including malaria., Hypothesis/purpose: Earlier studies on the plant's antiplasmodial activity were not assigned to any phytochemical with no quality assurance data. In this report, a recent chemically characterized extract and it's major constituent were investigated for in vitro antiplasmodial activity on chloroquine sensitive NF-54 strain. Furtherly, the potent extract and this constituent were assessed in vivo in Plasmodium berghei infected mice. The bioactive phytochemical and enriched extract were also monitored against various oxidative stress parameters., Study Design/method: The extract characterization was done by the quantitative analysis of eight phytochemicals using gradient reverse phase HPLC method. In vitro antiplasmodial activity was evaluated on chloroquine sensitive NF-54 strain by the determination of pfLDH activity. In vivo activity of the most potent extract and constituent were evaluated in P. berghei infected mice upon oral administration. The estimation of oxidative stress was done by monitoring various enzymatic and non-enzymatic parameters., Results: The ethyl acetate extract of leaves (IC 50 9.00 ± 0.68 µg/ml) and fraxetin (IC 50 19.21 ± 1.04 µM) were the most effective in in vitro assays therefore selected for in vivo tests. The administration of the ethyl acetate extract of leaves and fraxetin to the infected mice resulted in significant (p < .05) suppression of parasitaemia as evidenced by a 70.44 ± 2.58% to 78.77 ± 3.43% reduction compared to non-infected group. In addition, a two-fold increase in mean survival time, a significant (p < .05) reduction in lipid peroxidation and an elevation in glutathione, catalase and superoxide dismutase were also observed in treated mice. The post-infection treatment also led to an augmentation of endogenous antioxidant enzymes (GST, GR, GPx) with respect to the infected control. A significant (p < .05) elevation in serum Nrf2-antioxidant response element level responsible for the activation of endogenous enzymes was also observed., Conclusion: It was evident from the experiments that ethyl acetate extract of L. inermis and fraxetin were able to suppress the oxidative damage by augmenting endogenous antioxidant system and thus ameliorated the plasmodium infection in mice., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Background: Staphylococcus aureus (SA), is a major human pathogen causing wide range of clinical infections, which has been further complicated by drug resistance like methicillin resistant S. aureus (MRSA), vancomycin intermediate S. aureus (VISA)/vancomycin resistant S. aureus (VRSA), etc. The present study was aimed at determining anti-staphylococcal potential of citral against drug resistant clinical isolates alone and in combination with antibiotics., Purpose: To assess the potential of citral in combination with norfloxacin in treating drug resistant infections of SA., Study Design: In the present study, synergistic interaction of citral and norfloxacin against drug resistant SA strains was evaluated. Further the efficacy and possible mechanism of action of the combination was also evaluated using in vitro and in vivo assays., Method: The anti-staphylococcal activity of each of the monoterpene and the antibiotic was determined in terms of MIC and the effective concentration of both compounds in combination was obtained by checkerboard assay. In vivo efficacy and oral acute toxicity was evaluated in Swiss albino mice model. To understand the mechanism of action, time-kill curve, bacteriolysis, leakage, membrane depolarization, salt tolerance and ethidium bromide efflux assays were performed., Results: Citral was found effective against clinical isolates of SA with MIC values ranging from 75 to 150 µg ml -1 exhibiting bacteriostatic activity. Citral interacted synergistically, reducing MIC of norfloxacin up to 32-folds with FICI ≤ 0.50. Citral did not affect cell wall, but could damage cell membrane, inhibit efflux pump and affect the membrane potential. Citral could reduce the staphylococcal load of spleen and liver tissues in a dose-dependent manner which was further reduced when used in combination with norfloxacin. Citral did not exhibit any mortality or morbidity up to 500 mg kg -1 body weight and found to prolong the post-antibiotic effect of norfloxacin., Conclusion: Based on these observations, citral could be a lead candidate phytomolecule for further developing it into an anti-staphylococcal agent. The observations of combination study will help in reducing the burden of antibiotics leading to delayed resistance development., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

The study manifests the immunoadjuvant potential of saponin rich fraction from Asparagus racemosus in terms of cellular and humoral immune response that can be exploited against microbial infections. Asparagus racemosus (AR) has been attributed as an adaptogen and rasayana in traditional medication systems for enhancing the host defence mechanism. Spectrophotometric and HPTLC analysis ensured the presence of saponins. The saponin rich fractions were tested for immunoadjuvant property in ovalbumin immunised mice for the humoral response, quantified in terms of prolonged antibody production upto a duration of 56days. Proinflammatory cytokines (IL-6 and TNF) were estimated for the cellular immune response in LPS stimulated primary murine macrophages. The safety evaluation in terms of cytotoxicity and allergic response has also been evaluated through in-vitro (MTT) and in-vivo (IgE) respectively. ARS significantly inhibited the pro-inflammatory cytokines, in LPS stimulated murine macrophages with no intrinsic cytotoxicity. The significant increase in IgG production infers the utility of ARS for prolonged humoral response. Further, the antigen specific response of IL-12 at early stage and IgE titres also suggests the generation of cellular immune response and low allergic reaction respectively, as compared to conventional adjuvants. IL-6 and TNF fluctuations in LPS stimulated and non-stimulated macrophages along with IgG and IL-12 also confirmed the Th1/Th2 modulating effect of ARS. The study indicates potential effect of ARS as an adjuvant for the stimulation of cellular immune response in addition to generating a sustained adaptive response without any adverse effects paving way for further validation with pathogenic organisms., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Isoliquiritigenin (ISL) and liquiritigenin (LTG) are structurally related flavonoids found in a variety of plants. Discovery of novel antimicrobial combinations for combating methicillin-resistant Staphylococcus aureus (MRSA) infections is of vital importance in the post-antibiotic era. The present study was taken to explore the in vitro and in vivo combination effect of LTG and ISL with β-lactam antibiotics (penicillin, ampicillin and oxacillin) against mec A-containing strains of MRSA. Minimum inhibitory concentration (MIC) of both LTG and ISL exhibited significant anti-MRSA activity (50-100 µg/mL) against clinical isolates of MRSA. The result of in vitro combination study showed that ISL significantly reduced MIC of β-lactam antibiotics up to 16-folds [∑ fractional inhibitory concentration (FIC) 0.312-0.5], while LTG reduced up to 8-folds (∑FIC 0.372-0.5). Time kill kinetics at graded MIC combinations (ISL/LTG + β-lactam) indicated 3.27-9.79-fold and 2.59-3.48-fold reduction in the growth of clinical isolates of S. aureus respectively. In S. aureus-infected Swiss albino mice model, combination of ISL with oxacillin significantly (p < 0.05, p < 0.01, p < 0.001) lowered the systemic microbial burden in blood, liver, kidney, lung and spleen tissues in comparison with ISL, oxacillin alone as well as untreated control. Considering its synergistic antibacterial effect, we suggest both ISL and LTG as promising compounds for the development of novel antistaphylococcal combinations. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Staphylococcus aureus infections are raising serious concern across the world. The effectiveness of conventional drugs is continuously decreasing due to global emergence of multidrug resistance (MDR) and therefore, new resistance-modifying agents (RMAs) are highly needed., Hypothesis: Clerodane diterpene 16α-hydroxycleroda-3,13(14)-Z-dien-15,16-olide (CD) from leaves of Polyalthia longifolia (Sonn.) Thwaites (Annonaceae) as RAM will be useful in improving the current treatment strategies for staphylococcal infections., Study Design: In the present study, we determine the resistance-modifying activity of CD using clinical isolates of MRSA. Further, the influence of CD on innate immune response was also evaluated in vitro and in vivo. The nature of potential interactions was determined by fractional inhibitory concentration indices (FICIs) calculated from microdilution assays and time-kill curves., Results: The result of in vitro combination study showed that CD significantly reduced MIC of fluoroquinolones up to 16-folds (FICI 0.315-0.500), while in S. aureus infected Swiss albino mice model, combination of CD with norfloxacin, significantly (p<0.01, p<0.001) lowered the systemic microbial burden in blood, liver, kidney, lung and spleen tissues in comparison to CD, norfloxacin alone as well as untreated control. Flow cytometry analysis clearly showed that CD significantly inhibited EtBr efflux and extended post-antibiotic effect. In qRT-PCR analysis, CD alone as well as in combination, significantly modulated the expression of various efflux pump genes including norA up to 2-fold in clinical isolate MRSA-ST2071. Further, the in vitro combination study of the CD (10, 5, 2.5µg/ml) along with the norfloxacin (10µg/ml) depicted a significant decline in the pro-inflammatory cytokines, IL6 and TNF-α. In septic shock mice model, CD did not exhibit any significant changes in the level of pro-inflammatory cytokines., Conclusion: This is the first report on drug resistance-modifying potential of CD through inhibition of MDR efflux pump., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Diarylheptanoids from Alnus nepalensis leaves have been reported for promising activity against filariasis, a mosquito-borne disease, and this has prompted us to investigate its anti-malarial and safety profile using in-vitro and in-vivo bioassays. A. nepalensis leaf extracts were tested in-vitro against chloroquine-sensitive Plasmodium falciparum NF54 by measuring the parasite specific lactate dehydrogenase activity. Among all, the chloroform extract (ANC) has shown promising anti-plasmodial activity (IC50 8.06 ± 0.26 µg/mL). HPLC analysis of ANC showed the presence of diarylheptanoids. Efficacy and safety of ANC were further validated in in-vivo system using Plasmodium berghei-induced malaria model and acute oral toxicity in mice. Malaria was induced by intra-peritoneal injection of P. berghei infected red blood cells to the female Balb/c mice. ANC was administered orally at doses of 100 and 300 mg/kg/day following Peter's 4 day suppression test. Oral administration of ANC showed significant reduction of parasitaemia and increase in mean survival time. It also attributed to inhibition of the parasite induced pro-inflammatory cytokines as well as afford to significant increase in the blood glucose and haemoglobin level when compared with vehicle-treated infected mice. In-vivo safety evaluation study revealed that ANC is non-toxic at higher concentration. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

The purpose of the present study was to study the synergy potential of gallic acid-based derivatives in combination with conventional antibiotics using multidrug resistant cultures of Escherichia coli. Gallic acid-based derivatives significantly reduced the MIC of tetracycline against multidrug resistant clinical isolate of E. coli. The best representative, 3-(3',4,'5'-trimethoxyphenyl)-4,5,6-trimethoxyindanone-1, an indanone derivative of gallic acid, was observed to inhibit ethidium bromide efflux and ATPase which was also supported by in silico docking. This derivative extended the post-antibiotic effect and decreased the mutation prevention concentration of tetracycline. This derivative in combination with TET was able to reduce the concentration of TNFα up to 18-fold in Swiss albino mice. This derivative was nontoxic and well tolerated up to 300 mg/kg dose in subacute oral toxicity study in mice. This is the first report of gallic acid-based indanone derivative as drug resistance reversal agent acting through ATP-dependent efflux pump inhibition.

The objective of the present study was to repurpose L-menthol, which is frequently used in oral health and topical formulations, for cancer therapeutics. In this article, we argue that monoterpenes such as L-menthol might offer veritable potentials in systems medicine, for example, as cheaper anti-cancer compounds. Other monoterpenes such as limonene, perillyl alcohol, and geraniol have been shown to induce apoptosis in various cancer cell lines, but their mechanisms of action are yet to be completely elucidated. Earlier, we showed that L-menthol modulates tubulin polymerization and apoptosis to inhibit cancer cell proliferation. In the present report, we used an apoptosis-related gene microarray in conjunction with proteomics analyses, as well as in silico interpretations, to study gene expression modulation in human adenocarcinoma Caco-2 cell line in response to L-menthol treatment. The microarray analysis identified caspase 10 as the important initiator caspase, instead of caspase 8. The proteomics analyses showed downregulation of HSP90 protein (also corroborated by its low transcript abundance), which in turn indicated inhibition of AKT-mediated survival pathway, release of pro-apoptotic factor BAD from BAD and BCLxL complex, besides regulation of other factors related to apoptosis. Based on the combined microarray, proteomics, and in silico data, a signaling pathway for L-menthol-induced apoptosis is being presented for the first time here. These data and literature analysis have significant implications for "repurposing" L-menthol beyond oral medicine, and in understanding the mode of action of plant-derived monoterpenes towards development of cheaper anticancer drugs in future.

Infectious diseases are one of the major causes of morbidity and mortality in children in developing and underdeveloped countries. Limited knowledge of targets (cell wall synthesis, replication, transcription, protein synthesis) for antibiotics and lack of novel antibiotics have lead to an emergence of different level of resistance in bacterial pathogens. Multidrug resistance is the phenomenon by which the bacteria exerts resistance against the two or more structurally unrelated drugs/antibiotics. A common goal in the post-genomic era is to identify novel targets/drugs for various life threatening bacterial pathogens. Nanoparticles are broadly defined as submicron colloidal particles of size less than 1μm. Nanoparticles of size less than 100nm are the most promising warheads to overcome microbial drug resistance because they can act as antibacterial/antibiotic modulating agents at the site of infection and may have more than one mode of action. These nanoparticles will be of immense help in transporting drugs directly at the infected sites. Thus prevent drug resistance development to a great extent. In this review, the key mechanisms of resistance in bacterial superbugs have been discussed as well as how nanoparticles can overcome them. It is hypothesized that the nanoparticles can overcome the drug resistance via a novel mechanism of action. Additionaly, nanopaticles may also work synergistically with antibiotics via increased uptake, decreased efflux and inhibition of biofilm formation. The degradation by metallo beta lactamases and synthesis of porins may also be facilitated through these nanoparticles.

Saraca asoca bark has been used in the Ayurvedic system of medicine for female urino-genital disorders. We have recently reported the isolation and characterization of several compounds as markers to develop HPLC profiling of its methanol and aqueous methanol extracts. Now, a HPLC-PDA inactive compound, (+)-pinitol has been isolated and characterized from the bark of this medicinally important tree. Pinitol is a well known bioactive compound for a variety of biological activities, including hypoglycemic and anti-inflammatory activities. A process for the isolation of relatively good concentration of (+)-pinitol from S. asoca bark has been developed and its in vitro anti TNF-α and anti-inflammatory activities against carragenan-induced edema confirmed. While conducting experiments on the possible agonistic activity, it was found that (+)-pinitol showed up to eight fold reduction in the doses of β-lactam antibiotics. The mechanism of its agonistic activity was studied by docking experiments which showed that different conformations of (+)-pinitol and antibiotics were actually in the same binding site with no significant change in the binding energy. These docking simulations, thus predict the possible binding mode of studied compounds and probable reason behind the synergistic effect of (+)-pinitol along with β-lactam antibiotics.

Antibacterial and synergy potential of naturally occurring indole alkaloids (IA): 10-methoxy tetrahydroalstonine (1), isoreserpiline (2), 10 and 11 demethoxyreserpiline (3), reserpiline (4), serpentine (5), ajmaline (6), ajmalicine (7), yohimbine (8), and α-yohimbine (9) was evaluated using microbroth dilution assay. Further, α-yohimbine (9) was chemically transformed into six semisynthetic derivatives (9A-9F), and their antibacterial and synergy potential in combination with nalidixic acid (NAL) against E. coli strains CA8000 and DH5α were also evaluated. The IA 1, 2, 4, 5, 9 and the derivative 9F showed eightfold reduction in the MIC of NAL against the DH5α and four- to eightfold reduction against CA8000. These alkaloids also reduced MIC of another antibiotic, tetracycline up to 8folds, against the MDREC-KG4, a multidrug-resistant clinical isolate of E. coli. Mode of action study of these alkaloids showed efflux pumps inhibitory potential, which was supported by their in silico binding affinity and downregulation of efflux pump genes. These results may be of great help in the development of cost-effective antibacterial combinations for treating patients infected with multidrug-resistant Gram-negative infections., (© 2015 John Wiley & Sons A/S.)

Glabridin a polyphenolic flavonoid from Glycyrrhiza glabra is known to possess several therapeutic properties. In the present study, we report for the first time the in vitro antibacterial activity (MIC values ranging from 3.12 to 25 μg/mL) of glabridin against multidrug-resistant clinical isolates of S. aureus by inducing oxidative stress. Increased levels of H2O2 and NO were observed in a dose-dependent manner after treatment of glabridin that further affected macromolecules such as DNA, lipids, and proteins. Surprisingly, glabridin was found to possess antioxidant properties when used at lower concentrations using three different methods including DPPH, FRAP, and SOD assays. These observations were further validated through the expression analysis of oxidative stress-responsive genes using qRT-PCR wherein glabridin was observed to up- and down-regulate these genes at lower and higher concentrations, respectively. In in vitro combination experiments, glabridin was found to reduce the MIC of different antibiotics such as norfloxacin, oxacillin, and vancomycin by up to 4-fold, while the MIC of glabridin itself was found to be reduced by up to 8-fold in the presence of antibiotics. A synergistic interaction was observed between norfloxacin and glabridin when used in combination against multidrug-resistant clinical isolate SA 4627 of Staphylococcus aureus at much lower concentrations, indicating the suitability of glabridin in combination therapy., (Copyright © 2015. Published by Elsevier Inc.)

As a part of our drug discovery program, ursolic acid was chemically transformed into six semi-synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with conventional antibiotic nalidixic acid against the nalidixic acid-sensitive and nalidixic acid-resistant strains of Escherichia coli. Although ursolic acid and its all semi-synthetic derivatives did not show antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration of nalidixic acid up to eightfold. The 3-O-acetyl-urs-12-en-28-isopropyl ester (UA-4) and 3-O-acetyl-urs-12-en-28-n-butyl ester (UA-5) derivatives of ursolic acid reduced the minimum inhibitory concentration of nalidixic acid by eightfold against nalidixic acid-resistant and four and eightfold against nalidixic acid-sensitive, respectively. The UA-4 and UA-5 were further evaluated for their synergy potential with another antibiotic tetracycline against the multidrug-resistant clinical isolate of Escherichia coli-KG4. The results showed that both these derivatives in combination with tetracycline reduced the cell viability in concentration-dependent manner by significantly inhibiting efflux pump. This was further supported by the in silico binding affinity of UA-4 and UA-5 with efflux pump proteins. These ursolic acid derivatives may find their potential use as synergistic agents in the treatment of multidrug-resistant Gram-negative infections., (© 2014 John Wiley & Sons A/S.)

A series of indolyl chalcones were synthesized and evaluated in vitro for their anticancer activity against four human cancer cell lines. Compounds 1a, 1b, 1d, 1f-1j, 2c, 2e, 2i showed significant cytotoxicity. Chalcones 1b and 1d were identified as the most potent and selective anticancer agents with IC50 values <1µg/ml and 1.51µg/ml, against WRL-68 cell line, respectively.

Conyza sumatrensis (Retz.) E.H. Walker (Cs) leaves are used for traditional treatment of malaria in Cameroon. However, the antimalarial activity of the leaf constituents of this plant is still unexplored. The aim of our investigation was to evaluate the antiplasmodial activity of some bioactive constituents from Cs leaves. Compounds were isolated from Cs leaves and structurally elucidated using extensive spectroscopic analysis. The in vitro antiplasmodial activity of the extracts and pure compounds were evaluated on chloroquine-sensitive strain (NF54) of Plasmodium falciparum. The in vivo assay was done by administering seven doses of extracts in mice infected with Plasmodium berghei K173 through oral route. Cytotoxicity of pure compounds on murine macrophage cells was performed through [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] (MTT) test. Hemolysis and lactate dehydrogenase assays were also carried out using standard procedures. The in silico prediction of bioactive constituents was performed through Autodock Vina. Polarity-based extracts from Cs were found to be active against P. falciparum (NF54) and P. berghei (K173) in vitro and in vivo respectively. Further, bioactivity-guided isolation of n-hexane fraction yielded three compounds, (1), (2) and (3) with IC50 of 34, 17.9 and 18μg/ml, respectively, while the ethyl acetate fraction afforded the fourth compound with an IC50 of 25μg/ml, indicating anti-malarial potential of Cs through PfLDH interaction without compromising normal cell growth. This study reports for the first time, the antiplasmodial activity of bioactive constituents from Cs and confirms its traditional use., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

A series of twenty one chalcone derivatives having indole moiety were synthesized and were evaluated against four human cancer cell lines. Indolyl chalcones 1a, 1b, 1d, 1f-1j, 2c, 2e, 2i showed good anticancer activity. Chalcones 1b and 1d were the most active and selective anticancer agents with IC50 values <1μg/ml and 1.51μg/ml, against WRL-68 cell line, respectively. Molecular mechanism was explored through in silico docking & ADMET studies.

Biotransformation of antimalarial drug artemisinin by fungi Rhizopus stolonifer afforded three sesquiterpenoid derivatives. The transformed products were 1α-hydroxyartemisinin (3), 3.0%, a new compound, 10β-hydroxyartemisinin, 54.5% (4) and deoxyartemisinin (2) in 9% yield. The fungus expressed high-metabolism activity (66.5%). The chemical structures of the compounds were elucidated by 1D, 2D NMR spectrometry and mass spectral data. The major compound 10β-hydroxyartemisinin (4) was chemically converted to five new derivatives 5-9. All the compounds 3-9 were subjected for in vitro anti-malarial activity. 10β-Hydroxy-12β-arteether (8), IC50 at 18.29nM was found to be 10 times better active than its precursor 4 (184.56nM) and equipotent antimalarial with natural drug artemisinin whereas the α-derivative 9 is 3 times better than 4 under in vitro conditions. Therefore, the major biotransformation product 4 can be exploited for further modification into new clinically potent molecules. The results show the versatility of microbial-catalyzed biotransformations leading to the introduction of a hydroxyl group at tertiary position in artemisinin in derivative (3)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)