International Journal of Medicinal Chemistry The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. A Review on Platensimycin: A Selective FabF Inhibitor Thu, 28 Jan 2016 08:58:08 +0000 Emerging resistance to existing antibiotics is an inevitable matter of concern in the treatment of bacterial infection. Naturally occurring unique class of natural antibiotic, platensimycin, a secondary metabolite from Streptomyces platensis, is an excellent breakthrough in recent antibiotic research with unique structural pattern and significant antibacterial activity. β-Ketoacyl-(acyl-carrier-protein (ACP)) synthase (FabF) whose Gram-positive bacteria need to biosynthesize cell membranes is the target of inhibition of platensimycin. So, isolation, retrosynthetic analysis, synthesis of platensimycin, and analogues of platensimycin synthesized till today are the objectives of this review which may be helpful to further investigate and to reveal untouched area on this molecule and to obtain a potential antibacterial lead with enhanced significant antibacterial activity. Manik Das, Partha Sakha Ghosh, and Kuntal Manna Copyright © 2016 Manik Das et al. All rights reserved. Antibacterial Properties of Alkaloid Extracts from Callistemon citrinus and Vernonia adoensis against Staphylococcus aureus and Pseudomonas aeruginosa Wed, 20 Jan 2016 07:59:15 +0000 The development of new antibiotics from new chemical entities is becoming more and more expensive, time-consuming, and compounded by emerging strains that are drug resistant. Alkaloids are plant secondary metabolites which have been shown to have potent pharmacological activities. The effect of alkaloids from Callistemon citrinus and Vernonia adoensis leaves on bacterial growth and efflux pump activity was evaluated on Staphylococcus aureus and Pseudomonas aeruginosa. At a concentration of 1.67 mg/mL, the alkaloids inhibited bacterial growth with comparable effects to ampicillin, a standard antibiotic. The alkaloids from C. citrinus were the most potent against S. aureus with an MIC of 0.0025 mg/mL and MBC of 0.835 mg/mL. It was shown that effects on P. aeruginosa by both plant alkaloids were bacteriostatic. P. aeruginosa was most susceptible to drug efflux pump inhibition by C. citrinus alkaloids which caused an accumulation of Rhodamine 6G of 121% compared to the control. Thus, C. citrinus alkaloids showed antibacterial activity as well as inhibiting ATP-dependent transport of compounds across the cell membrane. These alkaloids may serve as potential courses of compounds that can act as lead compounds for the development of plant-based antibacterials and/or their adjunct compounds. Donald Mabhiza, Tariro Chitemerere, and Stanley Mukanganyama Copyright © 2016 Donald Mabhiza et al. All rights reserved. In Silico Designing and Analysis of Inhibitors against Target Protein Identified through Host-Pathogen Protein Interactions in Malaria Mon, 18 Jan 2016 12:29:50 +0000 Malaria, a life-threatening blood disease, has been a major concern in the field of healthcare. One of the severe forms of malaria is caused by the parasite Plasmodium falciparum which is initiated through protein interactions of pathogen with the host proteins. It is essential to analyse the protein-protein interactions among the host and pathogen for better understanding of the process and characterizing specific molecular mechanisms involved in pathogen persistence and survival. In this study, a complete protein-protein interaction network of human host and Plasmodium falciparum has been generated by integration of the experimental data and computationally predicting interactions using the interolog method. The interacting proteins were filtered according to their biological significance and functional roles. α-tubulin was identified as a potential protein target and inhibitors were designed against it by modification of amiprophos methyl. Docking and binding affinity analysis showed two modified inhibitors exhibiting better docking scores of −10.5 kcal/mol and −10.43 kcal/mol and an improved binding affinity of −83.80 kJ/mol and −98.16 kJ/mol with the target. These inhibitors can further be tested and validated in vivo for their properties as an antimalarial drug. Monika Samant, Nidhi Chadha, Anjani K. Tiwari, and Yasha Hasija Copyright © 2016 Monika Samant et al. All rights reserved. Synthesis and Anti-Inflammatory Activity of Some O-Propargylated-N-acetylpyrazole Derived from 1,3-Diarylpropenones Mon, 11 Jan 2016 13:34:54 +0000 In search of novel effective potent therapeutic agents delivered by oral route for inflammation treatment, some novel O-propargylated-N-acetylpyrazole analogs (5a–j) were prepared by treating N-acetylpyrazole (4a–j) derived from 1,3-diarylpropenones (3a–j) with propargyl bromide. Claisen-Schmidt condensation of a series of substituted aryl ketones 1 and benzaldehydes 2 in glacial acetic acid afforded 1,3-diarylpropenones which on further treatment with hydrazine hydrate in acetic acid under reflux conditions afforded 1-acetyl-3,5-diaryl-4,5-dihydro(1H)pyrazoles (4a–j). The products were characterized by using spectroscopic techniques such as IR and NMR. In addition, the in vivo anti-inflammatory activity of the synthesized compounds was determined using the carrageenan-induced paw oedema method in rats. Ashwani Kumar Dhingra, Bhawna Chopra, Rameshwar Dass, and Sanjeev K. Mittal Copyright © 2016 Ashwani Kumar Dhingra et al. All rights reserved. p-Sulfonic Acid Calix[4]arene as an Efficient Catalyst for One-Pot Synthesis of Pharmaceutically Significant Coumarin Derivatives under Solvent-Free Condition Sun, 20 Dec 2015 12:52:02 +0000 One-pot and efficient protocol for preparation of some potent pharmaceutically valuable coumarin derivatives under solvent-free condition via direct coupling using biologically nontoxic organocatalyst, calix[4]arene tetrasulfonic acid (CSA), was introduced. Calix[4]arene sulfonic acid has been incorporated lately as a magnificent and recyclable organocatalyst for the synthesis of some organic compounds. Nontoxicity, solvent-free conditions, good-to-excellent yields for pharmaceutically significant structures, and especially ease of catalyst recovery make this procedure valuable and environmentally benign. Hamed Tashakkorian, Moslem Mansour Lakouraj, and Mona Rouhi Copyright © 2015 Hamed Tashakkorian et al. All rights reserved. A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model Tue, 10 Nov 2015 07:27:17 +0000 An updated model of the GABA(A) benzodiazepine receptor pharmacophore of the α5-BzR/GABA(A) subtype has been constructed prompted by the synthesis of subtype selective ligands in light of the recent developments in both ligand synthesis, behavioral studies, and molecular modeling studies of the binding site itself. A number of BzR/GABA(A) α5 subtype selective compounds were synthesized, notably α5-subtype selective inverse agonist PWZ-029 (1) which is active in enhancing cognition in both rodents and primates. In addition, a chiral positive allosteric modulator (PAM), SH-053-2′F-R-CH3 (2), has been shown to reverse the deleterious effects in the MAM-model of schizophrenia as well as alleviate constriction in airway smooth muscle. Presented here is an updated model of the pharmacophore for α5β2γ2 Bz/GABA(A) receptors, including a rendering of PWZ-029 docked within the α5-binding pocket showing specific interactions of the molecule with the receptor. Differences in the included volume as compared to α1β2γ2, α2β2γ2, and α3β2γ2 will be illustrated for clarity. These new models enhance the ability to understand structural characteristics of ligands which act as agonists, antagonists, or inverse agonists at the Bz BS of GABA(A) receptors. Terry Clayton, Michael M. Poe, Sundari Rallapalli, Poonam Biawat, Miroslav M. Savić, James K. Rowlett, George Gallos, Charles W. Emala, Catherine C. Kaczorowski, Douglas C. Stafford, Leggy A. Arnold, and James M. Cook Copyright © 2015 Terry Clayton et al. All rights reserved. Synthesis and Biological Activity of Arylspiroborate Salts Derived from Caffeic Acid Phenethyl Ester Thu, 05 Mar 2015 11:07:23 +0000 Two novel boron compounds containing caffeic acid phenethyl ester (CAPE) derivatives have been prepared and characterized fully. These new compounds and CAPE have been investigated for potential antioxidant and antimicrobial properties and their ability to inhibit 5-lipoxygenase and whether chelation to boron improves their biological activity. Sodium salt 4 was generally more active than ammonium salt 5 in the biological assays and surpassed the radical scavenging ability of CAPE. Compounds 4 and 5 were more active than CAPE and Zileuton in human polymorphonuclear leukocytes. These results clearly show the effectiveness of the synthesized salts as transporter of CAPE. Martin J. G. Hébert, Andrew J. Flewelling, Trevor N. Clark, Natalie A. Levesque, Jacques Jean-François, Marc E. Surette, Christopher A. Gray, Christopher M. Vogels, Mohamed Touaibia, and Stephen A. Westcott Copyright © 2015 Martin J. G. Hébert et al. All rights reserved. Design and Synthesis of Novel Hybrid Molecules against Malaria Thu, 05 Feb 2015 08:30:42 +0000 The effective treatment of malaria can be very complex: Plasmodium parasites develop in multiple stages within a complex life cycle between mosquitoes as vectors and vertebrates as hosts. For the full and effective elimination of parasites, an effective drug should be active against the earliest stages of the Plasmodium infection: liver stages (reduce the progress of the infection), blood stages (cure the clinical symptoms), and gametocytes (inhibit the transmission cycle). Towards this goal, here we report the design, the synthetic methodology, and the characterization of novel hybrid agents with combined activity against Plasmodium liver stages and blood stages and gametocytes. The divergent synthetic approach allows the access to differently linked primaquine-chloroquine hybrid templates in up to eight steps. Melanie Lödige and Luisa Hiersch Copyright © 2015 Melanie Lödige and Luisa Hiersch. All rights reserved. Design and Synthesis of Pyrazole-3-one Derivatives as Hypoglycaemic Agents Wed, 04 Feb 2015 06:08:30 +0000 Pyrazole-3-one compounds were designed on the basis of docking studies of previously reported antidiabetic pyrazole compounds. The amino acid residues found during docking studies were used as guidelines for the modification of aromatic substitutions on pyrazole-3-one structure. Depending on the docking score, the designed compounds were selectively prioritized for synthesis. The synthesized compounds were subjected to in vivo hypoglycemic activity using alloxan induced diabetic rats and metformin as a standard. Compound 4 having sulphonamide derivative was found to be the most potent compound among the series. Prasanna A. Datar and Sonali R. Jadhav Copyright © 2015 Prasanna A. Datar and Sonali R. Jadhav. All rights reserved. Facile Synthesis, Characterization, and In Vitro Antimicrobial Screening of a New Series of 2,4,6-Trisubstituted-s-triazine Based Compounds Sat, 31 Jan 2015 16:50:50 +0000 A series of new 2,4,6-trisubstituted-s-triazine was synthesized, assessed for antimicrobial activity, and characterized by FTIR, 1HNMR, 13CNMR, and elemental analysis. The tested compounds, 4d, 4g, 4h, 4k, and 4n, have shown considerable in vitro antibacterial efficacy with reference to the standard drug ciprofloxacin (MIC 3.125 μgmL−1 against B. subtilis, E. coli, and K. pneumoniae). It was observed that compounds 4d and 4h displayed equipotent antibacterial efficacy against B. subtilis (MIC 3.125 μgmL−1) and S. aureus (MIC 6.25 μgmL−1). The studies demonstrated that the para-fluorophenylpiperazine substituted s-triazine (4n) was potent and exhibited broad spectrum antibacterial activity against S. epidermidis, K. pneumoniae, and P. aeruginosa with MIC of 6.25 μgmL−1 and for E. coli, it showed an MIC of 3.125 μgmL−1 equipotent with reference to the standard drug. Among all the compounds under investigation, compound 4g also demonstrated significant antifungal activity (3.125 μgmL−1) against C. albicans. Ravi Bhushan Singh, Nirupam Das, and Md. Kamaruz Zaman Copyright © 2015 Ravi Bhushan Singh et al. All rights reserved. Design and Synthesis of Novel Antileishmanial Compounds Wed, 21 Jan 2015 08:40:23 +0000 According to the WHO, infectious diseases, and in particular neglected tropical diseases in poor developing countries, still play a significant role in a vast number of deaths reported worldwide. Among them, leishmaniasis occurs as a complex and clinically diverse illness caused by protozoan Leishmania species which are transmitted through the bite of sandflies. They develop through a complex life cycle, from promastigotes in sandflies to amastigotes in humans. The severity of disease is determined by the type of infecting Leishmania species and also depends strongly on whether the parasite infection leads to a systemic involvement or not. Since the sensitivity towards diverse medicaments highly differs among the Leishmania species, it is advantageous to treat leishmaniasis with species-specific drugs. Towards this goal we report a synthetic methodology and characterization of novel small molecular agents active against both forms of L. major. This synthetic approach allows for rapid access to new active antileishmanial drug templates and their first derivatives in moderate to very good yields. Although the compounds reported here are bioactive, the detailed biological results are part of a more comprehensive study and will be reported separately by our collaborators. Melanie Loedige Copyright © 2015 Melanie Loedige. All rights reserved. Synthesis and Structural Activity Relationship Study of Antitubercular Carboxamides Tue, 30 Dec 2014 06:06:26 +0000 The unusual structure and chemical composition of the mycobacterial cell wall, the tedious duration of therapy, and resistance developed by the microorganism have made the recurrence of the disease multidrug resistance and extensive or extreme drug resistance. The prevalence of tuberculosis in synergy with HIV/AIDS epidemic augments the risk of developing the disease by 100-fold. The need to synthesize new drugs that will shorten the total duration of effective treatment and/or significantly reduce the dosage taken under DOTS supervision, improve on the treatment of multidrug-resistant tuberculosis which defies the treatment with isoniazid and rifampicin, and provide effective treatment for latent TB infections which is essential for eliminating tuberculosis prompted this review. In this review, we considered the synthesis and structure activity relationship study of carboxamide derivatives with antitubercular potential. D. I. Ugwu, B. E. Ezema, F. U. Eze, and D. I. Ugwuja Copyright © 2014 D. I. Ugwu et al. All rights reserved. Synthetic Antimicrobial Peptides Exhibit Two Different Binding Mechanisms to the Lipopolysaccharides Isolated from Pseudomonas aeruginosa and Klebsiella pneumoniae Sun, 28 Dec 2014 09:19:42 +0000 Circular dichroism and 1H NMR were used to investigate the interactions of a series of synthetic antimicrobial peptides (AMPs) with lipopolysaccharides (LPS) isolated from Pseudomonas aeruginosa and Klebsiella pneumoniae. Previous CD studies with AMPs containing only three Tic-Oic dipeptide units do not exhibit helical characteristics upon interacting with small unilamellar vesicles (SUVs) consisting of LPS. Increasing the number of Tic-Oic dipeptide units to six resulted in five analogues with CD spectra that exhibited helical characteristics on binding to LPS SUVs. Spectroscopic and in vitro inhibitory data suggest that there are two possible helical conformations resulting from two different AMP-LPS binding mechanisms. Mechanism one involves a helical binding conformation where the AMP binds LPS very strongly and is not efficiently transported across the LPS bilayer resulting in the loss of inhibitory activity. Mechanism two involves a helical binding conformation where the AMP binds LPS very loosely and is efficiently transported across the LPS bilayer resulting in an increase in inhibitory activity. Mechanism three involves a nonhelical binding conformation where the AMP binds LPS very loosely and is efficiently transported across the LPS bilayer resulting in an increase in inhibitory activity. Hanbo Chai, William E. Allen, and Rickey P. Hicks Copyright © 2014 Hanbo Chai et al. All rights reserved. Evaluation of 11 Scoring Functions Performance on Matrix Metalloproteinases Thu, 25 Dec 2014 07:24:34 +0000 Matrix metalloproteinases (MMPs) have distinctive roles in various physiological and pathological processes such as inflammatory diseases and cancer. This study explored the performance of eleven scoring functions (D-Score, G-Score, ChemScore, F-Score, PMF-Score, PoseScore, RankScore, DSX, and X-Score and scoring functions of AutoDock4.1 and AutoDockVina). Their performance was judged by calculation of their correlations to experimental binding affinities of 3D ligand-enzyme complexes of MMP family. Furthermore, they were evaluated for their ability in reranking virtual screening study results performed on a member of MMP family (MMP-12). Enrichment factor at different levels and receiver operating characteristics (ROC) curves were used to assess their performance. Finally, we have developed a PCA model from the best functions. Of the scoring functions evaluated, F-Score, DSX, and ChemScore were the best overall performers in prediction of MMPs-inhibitors binding affinities while ChemScore, Autodock, and DSX had the best discriminative power in virtual screening against the MMP-12 target. Consensus scorings did not show statistically significant superiority over the other scorings methods in correlation study while PCA model which consists of ChemScore, Autodock, and DSX improved overall enrichment. Outcome of this study could be useful for the setting up of a suitable scoring protocol, resulting in enrichment of MMPs inhibitors. Jamal Shamsara Copyright © 2014 Jamal Shamsara. All rights reserved. Molecular Modeling Studies of Thiophenyl C-Aryl Glucoside SGLT2 Inhibitors as Potential Antidiabetic Agents Wed, 10 Dec 2014 00:10:11 +0000 A QSAR study on thiophenyl derivatives as SGLT2 inhibitors as potential antidiabetic agents was performed with thirty-three compounds. Comparison of the obtained results indicated the superiority of the genetic algorithm over the simulated annealing and stepwise forward-backward variable method for feature selection. The best 2D QSAR model showed satisfactory statistical parameters for the data set (, , and pred_) with four descriptors describing the nature of substituent groups and the environment of the substitution site. Evaluation of the model implied that electron-rich substitution position improves the inhibitory activity. The good predictive 3D-QSAR models by k-nearest neighbor (kNN) method for molecular field analysis (MFA) have cross-validated coefficient value of 0.7663 and predicted value of 0.7386. The results have showed that thiophenyl groups are necessary for activity and halogen, bulky, and less bulky groups in thiophenyl nucleus enhanced the biological activity. These studies are promising for the development of novel SGLT2 inhibitor, which may have potent antidiabetic activity. Mukesh C. Sharma and Smita Sharma Copyright © 2014 Mukesh C. Sharma and Smita Sharma. All rights reserved. A Predictive HQSAR Model for a Series of Tricycle Core Containing MMP-12 Inhibitors with Dibenzofuran Ring Sun, 07 Dec 2014 08:08:04 +0000 MMP-12 is a member of matrix metalloproteinases (MMPs) family involved in pathogenesis of some inflammatory based diseases. Design of selective matrix MMPs inhibitors is still challenging because of binding pocket similarities among MMPs family. We tried to generate a HQSAR (hologram quantitative structure activity relationship) model for a series of MMP-12 inhibitors. Compounds in the series of inhibitors with reported biological activity against MMP-12 were used to construct a predictive HQSAR model for their inhibitory activity against MMP-12. The HQSAR model had statistically excellent properties and possessed good predictive ability for test set compounds. The HQSAR model was obtained for the 26 training set compounds showing cross-validated value of 0.697 and conventional value of 0.986. The model was then externally validated using a test set of 9 compounds and the predicted values were in good agreement with the experimental results (). Then, the external validity of the model was confirmed by Golbraikh-Tropsha and metrics. The color code analysis based on the obtained HQSAR model provided useful insights into the structural features of the training set for their bioactivity against MMP-12 and was useful for the design of some new not yet synthesized MMP-12 inhibitors. Jamal Shamsara and Ahmad Shahir-Sadr Copyright © 2014 Jamal Shamsara and Ahmad Shahir-Sadr. All rights reserved. Synthesis Antimicrobial and Anticancer Evaluation of 1-Aryl-5-(o-methoxyphenyl)-2-S-benzyl Isothiobiurets Thu, 20 Nov 2014 13:46:53 +0000 A series of S-benzyl aryl thiourea were condensed with o-Methoxy phenyl isocyanate to yield respective isothiobiuret derivatives. The newly synthesized compounds were characterized by 1H-NMR, IR, and Mass Spectral studies and tested for biological activities. Mohammed M. Ansari, Shirish P. Deshmukh, Rizwan Khan, and Mohammed Musaddiq Copyright © 2014 Mohammed M. Ansari et al. All rights reserved. Synthesis, Physicochemical Properties, and Antimicrobial Studies of Iron (III) Complexes of Ciprofloxacin, Cloxacillin, and Amoxicillin Wed, 19 Nov 2014 10:30:22 +0000 Iron (III) complexes of ciprofloxacin, amoxicillin, and cloxacillin were synthesized and their aqueous solubility profiles, relative stabilities, and antimicrobial properties were evaluated. The complexes showed improved aqueous solubility when compared to the corresponding ligands. Relative thermal and acid stabilities were determined spectrophotometrically and the results showed that the complexes have enhanced thermal and acid stabilities when compared to the pure ligands. Antimicrobial studies showed that the complexes have decreased activities against most of the tested microorganisms. Ciprofloxacin complex, however, showed almost the same activity as the corresponding ligand. Job’s method of continuous variation suggested 1 : 2 metals to ligand stoichiometry for ciprofloxacin complex but 1 : 1 for cloxacillin complex. Fabian I. Eze, Uzoechi Ajali, and Pius O. Ukoha Copyright © 2014 Fabian I. Eze et al. All rights reserved. Chemical Characteristics, Synthetic Methods, and Biological Potential of Quinazoline and Quinazolinone Derivatives Thu, 13 Nov 2014 00:00:00 +0000 The heterocyclic fused rings quinazoline and quinazolinone have drawn a huge consideration owing to their expanded applications in the field of pharmaceutical chemistry. Quinazoline and quinazolinone are reported for their diversified biological activities and compounds with different substitutions bring together to knowledge of a target with understanding of the molecule types that might interact with the target receptors. Quinazolines and quinazolinones are considered as an important chemical for the synthesis of various physiological significance and pharmacological utilized molecules. Quinazolines and quinazolinone are a large class of biologically active compounds that exhibited broad spectrum of biological activities such as anti-HIV, anticancer, antifungal, antibacterial, antimutagenic, anticoccidial, anticonvulsant, anti-inflammatory, antidepressant, antimalarial, antioxidant, antileukemic, and antileishmanial activities and other activities. Being considered as advantaged scaffold, the alteration is made with different substituent. Mohammad Asif Copyright © 2014 Mohammad Asif. All rights reserved. Mannich Bases: An Important Pharmacophore in Present Scenario Wed, 12 Nov 2014 08:44:10 +0000 Mannich bases are the end products of Mannich reaction and are known as beta-amino ketone carrying compounds. Mannich reaction is a carbon-carbon bond forming nucleophilic addition reaction and is a key step in synthesis of a wide variety of natural products, pharmaceuticals, and so forth. Mannich reaction is important for the construction of nitrogen containing compounds. There is a number of aminoalkyl chain bearing Mannich bases like fluoxetine, atropine, ethacrynic acid, trihexyphenidyl, and so forth with high curative value. The literature studies enlighten the fact that Mannich bases are very reactive and recognized to possess potent diverse activities like anti-inflammatory, anticancer, antifilarial, antibacterial, antifungal, anticonvulsant, anthelmintic, antitubercular, analgesic, anti-HIV, antimalarial, antipsychotic, antiviral activities and so forth. The biological activity of Mannich bases is mainly attributed to α, β-unsaturated ketone which can be generated by deamination of hydrogen atom of the amine group. Suman Bala, Neha Sharma, Anu Kajal, Sunil Kamboj, and Vipin Saini Copyright © 2014 Suman Bala et al. All rights reserved. Protective Effect of Selected Medicinal Plants against Hydrogen Peroxide Induced Oxidative Damage on Biological Substrates Wed, 12 Nov 2014 00:00:00 +0000 Oxidative stress is developed due to susceptibility of biological substrates to oxidation by generation of free radicals. In degenerative diseases, oxidative stress level can be reduced by antioxidants which neutralize free radicals. Primary objective of this work was to screen four medicinal plants, namely, Andrographis paniculata, Costus speciosus, Canthium parviflorum, and Abrus precatorius, for their antioxidant property using two biological substrates—RBC and microsomes. The antioxidative ability of three solvent extracts, methanol (100% and 80%) and aqueous leaf extracts, was studied at different concentrations by thiobarbituric acid reactive substances method using Fenton’s reagent to induce oxidation in the substrates. The polyphenol and flavonoid content were analyzed to relate with the observed antioxidant effect of the extracts. The phytochemical screening indicated the presence of flavonoids, polyphenols, tannins, and β-carotene in the samples. In microsomes, 80% methanol extract of Canthium and Costus and, in RBC, 80% methanol extract of Costus showed highest inhibition of oxidation and correlated well with the polyphenol and flavonoid content. From the results it can be concluded that antioxidants from medicinal plants are capable of inhibiting oxidation in biological systems, suggesting scope for their use as nutraceuticals. Namratha Pai Kotebagilu, Vanitha Reddy Palvai, and Asna Urooj Copyright © 2014 Namratha Pai Kotebagilu et al. All rights reserved. Development of Small Molecular Proteasome Inhibitors Using a Caenorhabditis elegans Screen Tue, 11 Nov 2014 08:25:29 +0000 We have developed a screening protocol to identify compounds with characteristics of small molecule proteasome inhibitors using the real-time analysis of the Caenorhabditis elegans germ line. This screen is able to identify compounds that induce germ line phenotypes characteristic of a reduction in proteasome function such as changes in polarity, aberrant nuclear morphology, and stimulation of apoptosis. This basic protocol is amenable to a high throughput (96-well) format and has been used successfully to identify multiple compounds for further analysis based on structural elements from the naturally occurring compounds lactacystin and the β-lactone homologs omuralide and salinosporamide A. The further development of this assay system should allow for the generation of novel small molecule proteasome inhibitors in a genetically tractable whole animal amenable to biochemical analysis. Sudhir Nayak, Michela Fiaschi, Dana King, Erica R. Tabakin, Lyndsay Wood, and David A. Hunt Copyright © 2014 Sudhir Nayak et al. All rights reserved. Nitro Derivatives of Naturally Occurring β-Asarone and Their Anticancer Activity Wed, 01 Oct 2014 00:00:00 +0000 β-Asarone (2, 4, 5-trimethoxy-(Z)-1-propenylbenzene) was obtained from Acorus calamus. Nitration of β-asarone with AgNO2/I2 in ether yielded 1-(2, 4, 5-trimethoxy phenyl)-2-nitropropene (1) but with NaNO2/I2 in ethylene glycol obtained 1-(2, 4, 5-trimethoxy phenyl)-1-nitropropene (2). Compound 2 was prepared for the first time and characterized using IR, 1H-NMR, 13C-NMR, and GC-MS spectra and it was converted into 1-(2, 4, 5-trimethoxy) phenyl-1-propanone (3) using modified Nef reaction. Based on 1D NOESY experiments, compounds 1 and 2 have been assigned E configuration. Compounds 1 and 2 were subjected to cytotoxic activity using five human cancer cell lines, namely, MCF-7, SW-982, HeLa, PC-3, and IMR-32 by MTT assay. Except in breast cancer line (MCF-7) compound 2 exhibited five- to tenfold increase in activity compared to β-asarone and twofold increase over compound 1. Suvarna Shenvi, Latha Diwakar, and G. Chandrasekara Reddy Copyright © 2014 Suvarna Shenvi et al. All rights reserved. Synthesis and Biological Evaluation of Aminonaphthols Incorporated Indole Derivatives Wed, 10 Sep 2014 00:00:00 +0000 An efficient one pot condensation of naphthols (1), 2,5-disubstituted indole-3-carboxaldehydes (2), and secondary amines (3) has been achieved using dichloromethane as a solvent, stirring at room temperature. Some of the new [(disubstituted amino)(5-substituted 2-phenyl-1H-indol-3-yl)methyl]naphthalene-ols (4) derivatives were prepared in good yields. The significant features of this method are simple work-up procedure, inexpensive nontoxic solvent, shorter reaction times, and excellent product yields. The structures of newly synthesized compounds (4a–r) are confirmed by their elemental analysis, FTIR, 1H and 13C NMR, and mass spectral data. These compounds were screened for their in vitro antioxidant, antimicrobial, antitubercular, and anticancer activities. Among the synthesized compounds (4a–r), the compound 4e exhibited highest activity for radical scavenging and ferric ions reducing antioxidant power activities; compounds 4b, 4h, and 4k showed good metal chelating activity. Compounds 4n and 4q showed excellent antimicrobial activities with MIC value 08 µg/mL against tested strains. Compounds 4h, 4k, 4n, and 4q exhibited promising antitubercular activity with MIC value 12.5 µg/mL. Compounds 4k and 4q exhibited 100% cell lysis at concentration 10 µg/mL against MDA-MB-231 (human adenocarcinoma mammary gland) cell lines. Saundane Anand Raghunath and Kirankumar Nandibeoor Mathada Copyright © 2014 Saundane Anand Raghunath and Kirankumar Nandibeoor Mathada. All rights reserved. Docking Studies and Biological Activity of Fosinopril Analogs Sun, 06 Jul 2014 06:48:37 +0000 The purpose of the present study was to determine the angiotensin-I converting enzyme inhibitory activity of few novel Fosinopril derivatives which were predicted to possess better ACE inhibitory activity and lesser side effects than the existing drug molecule. In vitro study was carried out to determine ACE inhibitory activity of six different Fosinopril analogs by spectrophotometric assay procedure. Analog A2 showed the highest activity compared to other analogs and as well as Fosinopril itself. Docking studies of the compounds were done with the help of VLife MDS 3.0 software using GRIP batch docking method to find out which derivative had a better docking with ACE. The compounds which showed the highest negative score in docking have also exhibited good ACE inhibitory activity. Jayant Choudary, Suvarna G. Kini, Sreedhara Ranganath Pai Karkala, and Muhammad Mubeen Copyright © 2014 Jayant Choudary et al. All rights reserved. Target Based Designing of Anthracenone Derivatives as Tubulin Polymerization Inhibiting Agents: 3D QSAR and Docking Approach Thu, 17 Apr 2014 10:54:08 +0000 Novel anthracenone derivatives were designed through in silico studies including 3D QSAR, pharmacophore mapping, and molecular docking approaches. Tubulin protein was explored for the residues imperative for activity by analyzing the binding pattern of colchicine and selected compounds of anthracenone derivatives in the active domain. The docking methodology applied in the study was first validated by comparative evaluation of the predicted and experimental inhibitory activity. Furthermore, the essential features responsible for the activity were established by carrying out pharmacophore mapping studies. 3D QSAR studies were carried out for a series of 1,5- and 1,8-disubstituted10-benzylidene-10H-anthracen-9-ones and 10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-one derivatives for their antiproliferation activity. Based on the pattern recognition studies obtained from QSAR results, ten novel compounds were designed and docked in the active domain of tubulin protein. One of the novel designed compounds “N1” exhibited binding energy −9.69 kcal/mol and predicted Ki 78.32 nM which was found to be better than colchicine. Abdul Samad, Moawiah M. Naffaa, Mohammed Afroz Bakht, Manav Malhotra, and Majid A. Ganaie Copyright © 2014 Abdul Samad et al. All rights reserved. Significance and Biological Importance of Pyrimidine in the Microbial World Sun, 23 Mar 2014 12:34:34 +0000 Microbes are unique creatures that adapt to varying lifestyles and environment resistance in extreme or adverse conditions. The genetic architecture of microbe may bear a significant signature not only in the sequences position, but also in the lifestyle to which it is adapted. It becomes a challenge for the society to find new chemical entities which can treat microbial infections. The present review aims to focus on account of important chemical moiety, that is, pyrimidine and its various derivatives as antimicrobial agents. In the current studies we represent more than 200 pyrimidines as antimicrobial agents with different mono-, di-, tri-, and tetrasubstituted classes along with in vitro antimicrobial activities of pyrimidines derivatives which can facilitate the development of more potent and effective antimicrobial agents. Vinita Sharma, Nitin Chitranshi, and Ajay Kumar Agarwal Copyright © 2014 Vinita Sharma et al. All rights reserved. A Novel Inhibitor of Mammalian Triosephosphate Isomerase Found by an In Silico Approach Sun, 23 Mar 2014 09:34:20 +0000 Triosephosphate isomerase (TIM) is an essential, highly conserved component of glycolysis. Tumors are often dependent on glycolysis for energy and metabolite production (the Warburg effect). Glycolysis inhibitors thus show promise as cancer treatments. TIM inhibition, unlike inhibition of other glycolysis enzymes, also produces toxic methylglyoxal targeted to regions of high glycolysis, an effect that might also be therapeutically useful. Thus TIM is an attractive drug target. A total of 338,562 lead-like molecules were analyzed computationally to find TIM inhibitors by an efficient “double screen” approach. The first fragment-sized compounds were studied using structure-based virtual screening to identify binding motifs for mammalian TIM. Subsequently, larger compounds, filtered to meet the binding criteria developed in the first analysis, were ranked using a second round of structure-based virtual screening. A compound was found that inhibited mammalian TIM in vitro in the micromolar range. Docking and molecular dynamics (MD) suggested that the inhibitor made hydrogen bond contacts with TIM catalytic residues. In addition, hydrophobic contacts were made throughout the binding site. All predicted inhibitor-TIM interactions involved TIM residues that were highly conserved. The discovered compound may provide a scaffold for elaboration of other inhibitors. Lorraine Marsh and Kaushal Shah Copyright © 2014 Lorraine Marsh and Kaushal Shah. All rights reserved. Experimental Design-Based Response Surface Methodology Optimization for Synthesis of β-Mercapto Carbonyl Derivatives as Antimycobacterial Drugs Catalyzed by Calcium Pyrophosphate Thu, 06 Mar 2014 11:09:10 +0000 A simple protocol for the efficient preparation of β-mercapto carbonyl derivatives as antimycobacterial drugs has been achieved via Thia-Michael reaction between chalcones derivatives and thiols in the presence of calcium pyrophosphate as a heterogeneous catalyst under mild reaction conditions. The central composite design was used to design an experimental program to provide data to model the effects of various factors on reaction yield . The variables chosen were catalyst weight , reaction time , and solvent volume . The mathematical relationship of reaction yield on the three significant independent variables can be approximated by a nonlinear polynomial model. Predicted values were found to be in good agreement with experimental values. The optimum reaction conditions for reaction model (chalcone and thiophenol) obtained by response surface were applied to other substrates. This procedure provides several advantages such as high yield, clean product formation, and short reaction time. Younes Abrouki, Abdelkader Anouzla, Hayat Loukili, Jamal Bennazha, Rabiaâ Lotfi, Ahmed Rayadh, My Abdellah Bahlaoui, Saïd Sebti, Driss Zakarya, and Mohamed Zahouily Copyright © 2014 Younes Abrouki et al. All rights reserved. Therapeutic Potential of Hydrazones as Anti-Inflammatory Agents Tue, 04 Mar 2014 09:06:24 +0000 Hydrazones are a special class of organic compounds in the Schiff base family. Hydrazones constitute a versatile compound of organic class having basic structure (R1R2C=NNR3R4). The active centers of hydrazone, that is, carbon and nitrogen, are mainly responsible for the physical and chemical properties of the hydrazones and, due to the reactivity toward electrophiles and nucleophiles, hydrazones are used for the synthesis of organic compound such as heterocyclic compounds with a variety of biological activities. Hydrazones and their derivatives are known to exhibit a wide range of interesting biological activities like antioxidant, anti-inflammatory, anticonvulsant, analgesic, antimicrobial, anticancer, antiprotozoal, antioxidant, antiparasitic, antiplatelet, cardioprotective, anthelmintic, antidiabetic, antitubercular, trypanocidal, anti-HIV, and so forth. The present review summarizes the efficiency of hydrazones as potent anti-inflammatory agents. Anu Kajal, Suman Bala, Neha Sharma, Sunil Kamboj, and Vipin Saini Copyright © 2014 Anu Kajal et al. All rights reserved.