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Tuberculosis (TB) caused by the Mycobacterium tuberculosis (MTB) pathogen is a serious contagious illness that endangers the public's health. However, TB is treatable but due to the result of ineffective and protracted medication, MDR‐MTB and XDR‐MTB were able to develop, making their eradication highly challenging and necessitating potential treatments to be cured. This study aimed to identify the novel inhibitor for the InhA enzyme, a potential target of MTB. Initially, 2721 phytochemicals libraries were screened for ADME/Tox profiling and 49 phytochemicals were filtered out. Moreover, these phytochemicals with reference inhibitor triclosan were docked against InhA (PDB ID: 1BVR)., were showing binding energies ranging from −9.16–−6.3 kcal/mol, whereas triclosan showed −6.90 kcal/mol of binding energy. The docking results reveal that irilone (−9.16 kcal/mol) and aurantio‐obtusin (−8.84 kcal/mol) exhibit promising binding energy and perfectly occupy the binding site of InhA. Furthermore, molecular dynamics simulation (MDS) and MMGBSA studies showed better affinities of selected compounds in terms of stability, compactness, flexibility, and total BFE in complexes with InhA. This study concluded that irilone and aurantio‐obtusin could be promising InhA inhibitors based on their impressive pharmacokinetic profiling, toxicity, binding affinity, and stability. However experimental validation is a subject of further research. [ABSTRACT FROM AUTHOR]

Design, synthesis, and bioactivity evaluation of novel mannich bases (2a‐2j) and triazole‐chalcone derivatives (7a‐7k) of Eugenol 1 were reported. Among all the derivatives tested for antiproliferative activity, di‐amine manich derivative 2b (32.92 μM), and 4‐methoxy chalcone triazole derivative 7d (33.05 μM) significantly inhibited HepG2 cell lines when compared to the standard doxorubicin (37.29 μM). Whereas most of the compounds such as diethylamine 2a (17.75 μM), (aminomethyl) methane diamine 2b (17.02 μM), and bis (chloromethyl) amine 2c (20.12 μM) showed moderate to better inhibition towards MCF‐7 cell lines. The synthesized analogues were also tested for antidiabetic and antiobesity potentials. Compounds 2f (55.50%), 2c (54.34%), 7g (55.5%), and 2a (55.5%) have shown moderate inhibitory potentials toward intestinal α‐glucosidase enzyme when compared to the standard Acarbose (72.86%). Likewise, compounds 7d (82.95%), 7f (76.19%), 7g (74.81%), 7e (74.81%), and 2g (72.50%) have shown significant to moderate inhibitory potentials toward Pancreatic lipase enzyme when compared to the standard orlistat (91.10%). ROS induces life‐threatening diseases like diabetes, cancer, etc., and antioxidants play a major role in controlling their production. Compounds 2c (99.81%), 2i (99.80%), 2d (99.26%), 2g (98.79%), and 2f (98.42%) have shown significant antioxidant profiles in ABTS assay when compared to the standard Trolox (99.07%). Further, In silico Molecular docking and pharmacokinetic screening of the eugenol derivatives complemented the in vitro results indicating the drug likeness of the obtained active compounds. [ABSTRACT FROM AUTHOR]

Indanocine, a potent anticancer investigational drug of National Cancer Institute‐USA, has been much discussed in recent years. Present communication aimed at total synthesis of indanocine and its close analogues. Total synthesis was improved by double yields than previously reported yields. Some of the benzylidene and 2‐benzyl derivatives with free rotation at C2 position exhibited potential cytotoxicities against various human cancer cell lines. Five such analogues exhibited potential antiproliferative effect against HCT‐116 and MIA PACA‐2 cell lines. Benzylindanocine 12i induced microtubule destabilization by occupying colchicine binding pocket of β‐tubulin. It also exhibited anti‐inflammatory activity by down‐regulating IL‐6 and TNF‐α. In Ehrlich ascites carcinoma model, 12i reduced 78.4% of EAC tumour in Swiss albino mice at 90 mg/kg (i.p.) dose. Further, in in vivo safety studies, 12i was found to be safe to rodents up to 1,000 mg/kg dose. Concomitant anticancer and anti‐inflammatory activity of benzylindanocine is distinctive, which suggests its further optimization for better efficacy and druggability. [ABSTRACT FROM AUTHOR]

Prostate cancer is fourth most abundant cancer type around the globe. Brevifoliol, a rearranged taxoid from Taxus walllichiana needles has been derivatized as C5 esters using Steglich esterification reaction. Seventeen diverse analogues were evaluated against a panel of human cancer cell lines by MTT assay. Among these, two of the semi‐synthetic analogues, that is, 13 and 16 exhibited potent cytotoxicity, selectively against PC‐3, prostate cancer cell lines. In cell cycle analysis, analogue 13 induced S and G2/M phase arrest and induced apoptosis by activating caspase‐3. Compound 13 showed moderate efficacy in in‐vivo Ehrlich ascites carcinoma in Swiss albino mice. Further, compound 13 was found to be safe in Swiss albino mice up to 1,000 mg/kg dose in acute oral toxicity. Brevifoliol ester 13 may further be optimized for better efficacy. [ABSTRACT FROM AUTHOR]

Diverse benzylidene indanones and their derivatives were synthesized as anticancer agents. Two of the analogues, that is 7 and 22, exhibited significant antiproliferative activity against several human cancer cell lines. Both the compounds possessed antimitotic activity and induced apoptosis in DLD1 colorectal adenocarcinoma cells through activation of caspase pathways. In cell cycle analysis, both the compounds induced predominantly G2/M phase arrest in DLD1 cells. Molecular docking studies revealed that compound 7 occupies colchicine binding pocket of β‐tubulin. Both the compounds were safe in acute oral toxicity in rodents. Both the compounds are further being optimized for better efficacy. [ABSTRACT FROM AUTHOR]

The quinolinate phosphoribosyl transferase (QPT) is a key enzyme that converts quinolinic acid into nicotinic acid mononucleotide. The QPT gene plays an essential role in the pyridine nucleotide cycle as well as in the biosynthetic pathway of the alkaloid nicotine. However, a clear role for QPT is yet to be characterized to validate the actual function of this gene in planta. In this study, an RNA interference (RNAi) approach was used to reveal the functional role of QPT. Transformation and analysis of the hairy roots (HRs) of the Nicotiana leaf explants was used, followed by plant regeneration and analysis. High-performance liquid chromatography (HPLC) analysis of the HRs and of the regenerated plants both revealed altered alkaloid biosynthetic cycle, with a substantially reduced content of nicotine and anabasine. The transgenic plants exhibited a significantly altered phenotype and growth pattern. Also, silencing of QPT led to a decrease in chlorophyll content, maximum quantum efficiency of PSII, net CO2 assimilation and starch content. Results clearly demonstrated that QPT was not only involved in the biosynthetic pathway of the alkaloids but also affected plant growth and development. Our results provide information to be considered when trying to engineer the secondary metabolite quality and quantity. [ABSTRACT FROM AUTHOR]

Benzylidene indanones have been designed and synthesized from gallic acid, a plant phenolic acid as possible anticancer agent. The best analogue of the series, that is, 3-(3′,4′,5′-trimethoxyphenyl)-4,5,6-trimethoxy-2-(4˝-nitrobenzylidene)-indan-1-one ( 8) exhibited potent cytotoxicity ( IC50=3-10 μ m) against several human cancer cell lines through microtubule destabilization ( IC50=1.54 μ m) after occupying colchicine-binding site of β-tubulin. In cell cycle analysis, compound 8 exerted G2/ M phase arrest in both MCF-7 and MDA- MB-231 cells and induced apoptosis. It reduced 34.8% solid tumor in in vivo Ehrlich ascite carcinoma in Swiss albino mice at 30 mg/kg dose. In acute oral toxicity experiment, it was tolerable up to 300 mg/kg doses in Swiss albino mice. The lead compound 8 needs to be optimized for better activity. [ABSTRACT FROM AUTHOR]

A series of new andrographolide-1,2,3-triazole derivatives, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, were synthesized from a natural bioactive labdane type diterpenoid, andrographolide. All the derivatives were screened against human cancer cell lines MCF7, MDA-MB-231, COLO205, HepG2, K562, Hela, and HEK293 to evaluate their cytotoxic activity. All the compounds showed anticancer activity selectively against K562 cell line, with IC50 values ranging from 8.00 to 17.11 µ M, and are inactive against the rest of the cell lines. Compounds 3c and 3d showed significant cytotoxicity among the synthesized derivatives. The in silico docking studies revealed compounds 3b and 3d with high binding affinity against the cancer target, transient receptor potential vanilloid 1. [ABSTRACT FROM AUTHOR]

Andrographolide and neoandrographolide are major bioactive molecules of Andrographis paniculata, a well-known medicinal plant. These molecules exhibited varying degrees of anti-inflammatory and anticancer activities in-vitro and in-vivo. Role of begomovirus protein C2/TrAP in biosynthesis of andrographolide was identified through molecular modeling, docking and predicted results were substantiated by in vitro studies. Homology molecular modeling and molecular docking were performed to study the binding conformations and different bonding behaviors, in order to reveal the possible mechanism of action behind higher accumulation of andrographolide. It was concluded that C2/TrAP inhibit the activation of SNF1-Related Protein Kinase-1 (SnRK1) in terpenoid pathway and removes the negative regulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) by SnRK1, leading to higher accumulation of andrographolide and neoandrographolide in begomovirus infected plants. The binding site residues of SnRK1 docked with C2/TrAP were found to be associated with ATP binding site, substrate binding site and activation loop. Predicted results were also validated by HPTLC. This study provides important insights into understanding the role of viral protein in altering the regulation of biosynthesis of andrographolide and could be used in future research to develop biomimetic methods for increasing the production of such phytometabolites having anti-cancerous and anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In our prior studies, we reported some known antitubercular drugs (rifampicin and streptomycin) and newly synthesized chalcone derivatives (16-26) tested in vitro against Mycobacterium tuberculosis H37Rv strain. Most of the tested compounds were efficient antimycobacterial agents showing minimum inhibitory concentration values ranging from 3.5 to 30 µg mL−1. In the present work, a quantitative structure-activity relationship (QSAR) study has been performed on these active chalcone derivatives to correlate their chemical structures with their observed inhibiting activity against M. tuberculosis. A QSAR model that is able to correlate well the antitubercular activity with the chemical structures of active chalcone derivatives 16, 24, 25a, 25c, and 26 has been developed, which is potentially helpful in the design of novel and more potent antitubercular agents. The r2 and rCV2 of a newly derived QSAR model were 0.89 and 0.84, respectively. The QSAR study indicates that chemical properties, viz. heat of formation (kcal mol−1), lowest unoccupied molecular orbital energy (eV), and amine, hydroxyl, and methyl groups counts, correlate well with the activity. In silico screening results for oral bioavailability and absorption, distribution, metabolism, excretion, and toxicity compliance showed that compounds 25a, 25c, and 24 were found active similar to rifampicin and streptomycin. The docking study for the exploration of mechanism of action showed high binding affinity of active derivatives. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The purpose of present investigation was to understand the drug resistance reversal mechanism of 4-hydroxy- α-tetralone ( 1) isolated from Ammannia spp. along with its semi-synthetic derivatives ( 1a- 1e) using multidrug resistant Escherichia coli ( MDREC). The test compounds did not show significant antibacterial activity of their own, but in combination, they reduced the minimum inhibitory concentration ( MIC) of tetracycline ( TET). In time kill assay, compound 1 and its derivative 1e in combination with TET reduced the cell viability in concentration dependent manner. Compounds 1 and 1e were also able to reduce the mutation prevention concentration of TET. Both compounds showed inhibition of ATP dependent efflux pumps. In real time polymerase chain reaction ( RT- PCR) study, compounds 1 and 1e alone and in combination with TET showed significant down expression of efflux pump gene ( yojI) encoding multidrug ATP binding cassettes ( ABC) transporter protein. Molecular mechanism was also supported by the in silico docking studies, which revealed significant binding affinity of compounds 1 and 1e with YojI. This study confirms that compound 1 and its derivative 1e are ABC efflux pump inhibitors which may be the basis for development of antibacterial combinations for the management of MDR infections from inexpensive natural product. [ABSTRACT FROM AUTHOR]

Plants posses a complex co-regulatory network which helps them to elicit a response under diverse adverse conditions. We used an in silico approach to identify the genes with both DRE and ABRE motifs in their promoter regions in Arabidopsis thaliana. Our results showed that Arabidopsis contains a set of 2,052 genes with ABRE and DRE motifs in their promoter regions. Approximately 72% or more of the total predicted 2,052 genes had a gap distance of less than 400 bp between DRE and ABRE motifs. For positional orientation of the DRE and ABRE motifs, we found that the DR form (one in direct and the other one in reverse orientation) was more prevalent than other forms. These predicted 2,052 genes include 155 transcription factors. Using microarray data from The Arabidopsis Information Resource (TAIR) database, we present 44 transcription factors out of 155 which are upregulated by more than twofold in response to osmotic stress and ABA treatment. Fifty-one transcripts from the one predicted above were validated using semiquantitative expression analysis to support the microarray data in TAIR. Taken together, we report a set of genes containing both DRE and ABRE motifs in their promoter regions in A. thaliana, which can be useful to understand the role of ABA under osmotic stress condition. [ABSTRACT FROM AUTHOR]

In the present work, quantitative structure-activity relationship (QSAR) models of camptothecin derivatives against DNA Topoisomerase-I (DNA Topo-I) were developed by multiple linear regression method using leave-one-out validation approach. The r2 and rCV2 of the model were 0.89 and 0.86, respectively. The QSAR study indicates that chemical descriptors, namely Connectivity Index (order 1, standard), Electron Affinity (eV), Molecular Weight, Group Count (ether) are correlated well with activity. Further, screening for drug likeness, ADME and toxicity showed that compound CPT9, CPT14, CPT20, CPT21 and CPT22 exhibits marked anticancer activity and possesses two times more potent than standard drug camptothecin. The docking study showed a high binding affinity of predicted active derivatives and showed H-bond formation with GLY363, ARG364, LYS374, GLN421, ARG488, and ASP-533 residues, therefore considered as more stable and potent anticancer compounds. The obtained results can be used for the design of novel potent and selective inhibitors of DNA Topo-I. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum, a causitive agent of malaria, is the third most prevalent factor for mortility in the world. Falciparum malaria is an example of evolutionary and balancing selection. Because of mutation and natural selection, the parasite has developed resistance to most of the existing drugs. Under such circumstances, there is a growing need to develop new molecular targets in P. falciparum. A four membrane bound organelles called apicoplast, very much similar to that of chloroplast of plants, have been found in parasite. Therefore, the proteins involved in metabolic pathways of apicoplasts are important drug targets. Among the pathways in apicoplast, fatty acid biosynthetic pathway is the most important metabolic pathway in P. falciparum. Several studies have explored the role of different proteins involved in this pathway and antimalarial compounds against this target. In this review, we have studied the role of different proteins in fatty acid metabolism and designing, synthesis and evaluation of compounds against the targets identified in fatty acid metabolic pathway. [ABSTRACT FROM AUTHOR]

Khan F, Li W, Habelitz S. Biophysical characterization of synthetic amelogenin C-terminal peptides. Eur J Oral Sci 2012; 120: 113-122. © 2012 Eur J Oral Sci Amelogenin plays a key role in the formation of the highly mineralized structure of tooth enamel. During the secretory stage, amelogenin is cleaved gradually by a protease, matrix metalloproteinase-20 (MMP-20), releasing hydrophilic C-terminal peptides. In this study, the biophysical properties of synthetic C-terminal peptides (of 28, 17, and 11 residues), mimicking native peptides, were explored in vitro. A sudden decrease was observed in the zeta (ζ)-potential upon the addition of calcium or phosphates, which was also accompanied by an increased aggregation propensity of the peptides. Under most of the experimental conditions, the particle size increased at a pH 2-3 units higher than the isoelectric point (pI) of the peptides, while the peptides existed as smaller particles (<2 nm) near their pI values and in the acidic range. They showed poor affinity for calcium and phosphates, comparable to full-length amelogenin and variants. The secondary structure determination showed that the 11-amino-acid peptide contained defined secondary structure comprising beta-sheets and turns. Atomic force microscopy analysis revealed the presence of thin, disk-like nanostructures of 54.4 nm diameter for the 28-amino-acid peptide and 54.9 nm diameter for the 11-amino acid peptide, whereas no definite structures were observed for the 17-amino-acid peptide. It is concluded that the amelogenin C-terminal peptides are capable of interacting with calcium and phosphate ions, of self-assembly into nanostructures, and may have some secondary structure, and hence may have some role in enamel synthesis. [ABSTRACT FROM AUTHOR]

Martinez-Avila OM, Wu S, Cheng Y, Lee R, Khan F, Habelitz S. Self-assembly of amelogenin proteins at the water-oil interface. Eur J Oral Sci 2011; 119 (Suppl. 1): 75-82. © 2011 Eur J Oral Sci Self-assembly of amelogenin plays a key role in controlling enamel biomineralization. Recently, we generated self-aligning nanoribbons of amelogenin in water-in-oil emulsions stabilized by the full-length protein (rH174). Here, we tested the hypothesis that the hydrophilic C-terminus is critical for self-assembly of amelogenin into nanoribbons. The self-assembled structures of two amelogenin cleavage products, rH163 and rH146, were compared with structures of rH174 at different pH values and degrees of saturation using atomic force microscopy, electron microscopy, and dynamic light scattering. We observed that the number density of rH174 nanoribbons increased significantly when the initial pH was raised from 4.5 to 5.6. Nanoribbons, as well as unique helical nanostructures, were also readily observed when amelogenin rH146 was used, but showed little tendency for parallel alignment and did not bundle into fibrils like rH174. In contrast, rH163 rarely formed nanoribbons but predominantly assembled into nanospheres under the same conditions. We conclude that the presence of a hydrophilic C-terminus may not be a prerequisite for nanoribbon formation but may be critical for ribbon alignment and subsequent fibril formation. These results highlight the contribution of the hydrophobic domain in the self-assembly of elongated structures of amelogenins. Molecular mechanisms governing these processes based on the formation of reverse micelles are discussed. [ABSTRACT FROM AUTHOR]

Natural coumarinolignoids isolated from the seeds of Cleome viscosa consist of a racemic mixture of cleomiscosins A, B and C. To screen out potential lead, anti-inflammatory activity of the isolated compounds was evaluated through molecular docking and QSAR studies by using reported in vivo activity of Swiss albino mice. Based on docking binding affinity, a possible mechanism of action has been hypothesized which constitute toll-like receptors (TLR-4), cluster of differentiation molecules (CDs), iNOS, COX-2 and STAT-6 proteins. It was very interesting to find that the 3D topology of the active site of COX-2 from the docking was in good agreement with QSAR model and in silico ADME/T parameters. A forward feed multiple linear regression model was developed with r2 = 0.92 and rCV2 = 0.87. This study showed that chemical descriptors, for example dipole vector- X, dipole vector- Y, steric energy, LUMO energy, size of smallest ring, size of largest ring and carboxyl group count, correlate reasonably well with experimental in vivo activity (logLD50). QSAR study indicates that dipole vector- Y and carboxyl group count have negative correlation with activity. Cleomiscosins also showed compliance with 95% of in silico ADME/T properties of available drugs, e.g. serum protein binding, blood-brain barrier, CNS activity, HERG K+ channel activity, apparent Caco-2 permeability, apparent MDCK permeability, skin permeability and human oral absorption in GI. Besides, toxicity screening study suggests that cleomiscosin molecules possess no toxicity risk parameters. This study offer useful references for understanding and molecular design of inhibitors with improved anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

The intrinsic fluorescence intensity of Fusarium solani lectin was quenched upon binding to mono- and oligosaccharides without any change in the emission maximum and it was used to determine association constants for several sugars and glycans. The lectin interacted very poorly with monosaccharides but well with disaccharides (T-antigen and LacNAc) with a distinction between β1→4 and β1→3 linkages. Among the monosaccharides, the interaction was observed only with Gal/GalNAc derivatives and not with Glc/Man derivatives. Thermodynamic studies revealed that the binding of the lectin with all the saccharides is enthalpically driven and exothermic in nature. Asialo-triantennary N-glycan and asialo-biantennary N-glycan showed higher affinity than monovalent LacNAc with significant increase in binding enthalpy, pointing towards the importance of multivalency in the lectin–ligand interactions. Time-resolved fluorescence measurement indicated the lectin has two lifetimes for tryptophan and the shorter lifetime is affected on ligand binding. [ABSTRACT FROM AUTHOR]

The effect of urea, guanidine thiocyanate, temperature and pH was studied on the conformational stability of Fusarium solani lectin. Equilibrium unfolding with chemical denaturants showed that the lectin was least stable at pH 12 and maximally stable at pH 8.0 near its pI (8.7). Guanidine thiocyanate (the concentration of denaturant at which the protein is half folded, D1/2 = 0.49 M at pH 12) was found to be an eight times stronger denaturant than urea (D1/2 = 3.88 M at pH 12). The unfolding curves obtained with fluorescence and CD measurements showed good agreement indicating a monophasic nature of unfolding and excluded the possibility of formation of any stable intermediate. The effect of pH on the lectin was found to be unusual as at acidic pH, the lectin showed a flexible tertiary structure with pronounced secondary structure, and retained its hemagglutinating activity. On the other hand, the lectin did not show any loss of conformation or activity upto 70°C for 15 min. Moreover, thermal denaturation did not result in the aggregation or precipitation of the protein even at high temperatures. Thermal denaturation was also carried out in the presence of a low concentration of guanidine thiocyanate. Change in the enthalpy of transition (ΔHm) varied linearly with transition temperature (Tm), which indicated that the heat capacity (ΔCp = 3.95 kJ · mol-1 · K-1) of the lectin remained constant during the unfolding. IUBMB Life, 59: 34–43, 2007 [ABSTRACT FROM AUTHOR]

DbMDR is non-redundant reference database of multidrug resistance (MDR) genes and their orthologs acting as potential drug targets. Drug resistance is a common phenomenon of pathogens, creating a serious problem of inactivation of drugs and antibiotics resulting in occurrence of diseases. Apart from other factors, the MDR genes present in pathogens are shown to be responsible for multidrug resistance. Much of the unorganized information on MDR genes is scattered across the literature and other web resources. Thus, consolidation of such knowledge about MDR genes into one database will make the drug discovery research more efficient. Mining of text for MDR genes has resulted into a large number of publications but in scattered and unorganized form. This information was compiled into a database, which enables a user not only to look at a particular MDR gene but also to find out putative homologs based on sequence similarity, conserved domains, and motifs in proteins encoded by MDR genes more efficiently. At present, DbMDR database contains 2843 MDR genes characterized experimentally as well as functionally annotated with cross-referencing search support. The DbMDR database () is a comprehensive resource for comparative study focused on MDR genes and metabolic pathway efflux pumps and intended to provide a platform for researchers for further research in drug resistance. [ABSTRACT FROM AUTHOR]

The purpose of present investigation was to understand the drug resistance reversal mechanism of 4-hydroxy-α-tetralone (1) isolated from Ammannia spp. along with its semi-synthetic derivatives (1a-1e) using multidrug resistant Escherichia coli (MDREC). The test compounds did not show significant antibacterial activity of their own, but in combination, they reduced the minimum inhibitory concentration (MIC) of tetracycline (TET). In time kill assay, compound 1 and its derivative 1e in combination with TET reduced the cell viability in concentration dependent manner. Compounds 1 and 1e were also able to reduce the mutation prevention concentration of TET. Both compounds showed inhibition of ATP dependent efflux pumps. In real time polymerase chain reaction (RT-PCR) study, compounds 1 and 1e alone and in combination with TET showed significant down expression of efflux pump gene (yojI) encoding multidrug ATP binding cassettes (ABC) transporter protein. Molecular mechanism was also supported by the in silico docking studies, which revealed significant binding affinity of compounds 1 and 1e with YojI. This study confirms that compound 1 and its derivative 1e are ABC efflux pump inhibitors which may be the basis for development of antibacterial combinations for the management of MDR infections from inexpensive natural product., (© 2013 John Wiley & Sons A/S.)