International Journal of Medicinal Chemistry The latest articles from Hindawi © 2018 , Hindawi Limited . All rights reserved. Correlation between Virtual Screening Performance and Binding Site Descriptors of Protein Targets Thu, 11 Jan 2018 00:00:00 +0000 Rescoring is a simple approach that theoretically could improve the original docking results. In this study AutoDock Vina was used as a docked engine and three other scoring functions besides the original scoring function, Vina, as well as their combinations as consensus scoring functions were employed to explore the effect of rescoring on virtual screenings that had been done on diverse targets. Rescoring by DrugScore produces the most number of cases with significant changes in screening power. Thus, the DrugScore results were used to build a simple model based on two binding site descriptors that could predict possible improvement by DrugScore rescoring. Furthermore, generally the screening power of all rescoring approach as well as original AutoDock Vina docking results correlated with the Maximum Theoretical Shape Complementarity (MTSC) and Maximum Distance from Center of Mass and all Alpha spheres (MDCMA). Therefore, it was suggested that, with a more complete set of binding site descriptors, it could be possible to find robust relationship between binding site descriptors and response to certain molecular docking programs and scoring functions. The results could be helpful for future researches aiming to do a virtual screening using AutoDock Vina and/or rescoring using DrugScore. Jamal Shamsara Copyright © 2018 Jamal Shamsara. All rights reserved. Synthesis, Antimicrobial, and Computational Evaluation of Novel Isobutylchalcones as Antimicrobial Agents Tue, 26 Dec 2017 07:32:06 +0000 A series of 25 new chalcones were synthesized by Claisen-Schmidt condensation, well characterized by spectroscopic data, and evaluated for their antibacterial and antifungal activities by serial tube dilution method. Among the compounds tested, A3 and A6 containing 2,4-dichlorophenyl and 2,4-difluorophenyl moiety, respectively, were found to be the most potent in the series against both bacterial and fungal strains with a MIC value of 16 µg/mL in each case. Further computational evaluation for antimicrobial activity was performed by atom based 3D-QSAR using PHASE™ software in order to have a correlation between the observed activities and predicted activities. The computational studies were in agreement with the in vitro antimicrobial results and had identified the most promising chalcones as antimicrobial agents and the responsible structural features for the proposed activity. Afzal Basha Shaik, Rajendra Prasad Yejella, and Shahanaaz Shaik Copyright © 2017 Afzal Basha Shaik et al. All rights reserved. Design, Synthesis, and Cytotoxicity Evaluation of Novel Griseofulvin Analogues with Improved Water Solubility Thu, 07 Dec 2017 06:30:59 +0000 Griseofulvin 1 is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Study of SAR of some griseofulvin analogues has led to the identification of 2′-benzyloxy griseofulvin 3, a more potent analogue which retards tumor growth through inhibition of centrosomal clustering. However, similar to griseofulvin 1, compound 3 exhibited poor aqueous solubility. In order to improve the poor water solubility, six new griseofulvin analogues 5–10 were synthesized and tested for their antiproliferative activity and water solubility. The semicarbazone 9 and aminoguanidine 10 analogues were the most potent against HCT116 and MCF-7 cell lines. In combination studies, compound 9 was found to exert synergistic effects with tamoxifen and 5-fluorouracil against MCF-7 and HCT116 cells proliferation, respectively. The flow cytometric analysis of effect of 9 on cell cycle progression revealed G2/M arrest in HCT116. In addition, compound 9 induced apoptosis in MCF-7 cells. Finally, all synthesized analogues revealed higher water solubility than griseofulvin 1 and benzyloxy analogue 3 in pH 1.2 and 6.8 buffer solutions. Ahmed K. Hamdy, Mahmoud M. Sheha, Atef A. Abdel-Hafez, and Samia A. Shouman Copyright © 2017 Ahmed K. Hamdy et al. All rights reserved. Usefulness of Urea as a Means of Improving the Solubility of Poorly Water-Soluble Ascorbyl Palmitate Mon, 06 Nov 2017 00:00:00 +0000 The aim of this study was to evaluate complexes of L-ascorbyl palmitate (ASCP) and urea (UR). This evaluation involved differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), near-infrared spectroscopy (NIR), a solubility test, a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging test, and a mushroom tyrosinase inhibition assay. Physicochemical evaluation revealed that ASCP/UR complexes form at a molar ratio of 1/12. The solubility test revealed that ASCP/UR complexes had increased solubility compared to ASCP. The DPPH radical scavenging test and mushroom tyrosinase inhibition assay revealed that the activity of ASCP/UR complexes was not impaired by complex formation. These results are probably due to the tetragonal crystal system of UR changing to a hexagonal crystal system and interaction with the alkyl group of ASCP. Yutaka Inoue, Daichi Niiyama, Isamu Murata, and Ikuo Kanamoto Copyright © 2017 Yutaka Inoue et al. All rights reserved. Fluorinated Adenosine A2A Receptor Antagonists Inspired by Preladenant as Potential Cancer Immunotherapeutics Thu, 19 Oct 2017 00:00:00 +0000 Antagonism of the adenosine receptor on T cells blocks the hypoxia-adenosinergic pathway to promote tumor rejection. Using an in vivo immunoassay based on the Concanavalin A mouse model, a series of antagonists were studied and identified preladenant as a potent lead compound for development. Molecular modeling was employed to assist drug design and subsequent synthesis of analogs and those of tozadenant, including fluorinated polyethylene glycol PEGylated derivatives. The efficacy of the analogs was evaluated using two in vitro functional bioassays, and compound 29, a fluorinated triethylene glycol derivative of preladenant, was confirmed as a potential immunotherapeutic agent. Gengyang Yuan, Tanner C. Jankins, Christopher G. Patrick Jr., Phaethon Philbrook, Olivia Sears, Stephen Hatfield, Michail Sitkovsky, Neil Vasdev, Steven H. Liang, Mary Jo Ondrechen, Michael P. Pollastri, and Graham B. Jones Copyright © 2017 Gengyang Yuan et al. All rights reserved. Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs Mon, 05 Jun 2017 00:00:00 +0000 Thiazolidinediones are a class of well-established antidiabetic drugs, also named as glitazones. Thiazolidinedione structure has been an important structural domain of research, involving design and development of new drugs for the treatment of type 2 diabetes. Extensive research on the mechanism of action and the structural requirements has revealed that the intended antidiabetic activity in type 2 diabetes is due to their agonistic effect on peroxisome proliferator-activated receptor (PPAR) belonging to the nuclear receptor super family. Glitazones have specific affinity to PPARγ, one of the subtypes of PPARs. Certain compounds under development have dual PPARα/γ agonistic activity which might be beneficial in obesity and diabetic cardiomyopathy. Interesting array of hybrid compounds of thiazolidinedione PPARγ agonists exhibited therapeutic potential beyond antidiabetic activity. Pharmacology and chemistry of thiazolidinediones as PPARγ agonists and the potential of newer analogues as dual agonists of PPARs and other emerging targets for the therapy of type 2 diabetes are presented. This review highlights the possible modifications of the structural components in the general frame work of thiazolidinediones with respect to their binding efficacy, potency, and selectivity which would guide the future research in design of novel thiazolidinedione derivatives for the management of type 2 diabetes. Neelaveni Thangavel, Mohammed Al Bratty, Sadique Akhtar Javed, Waquar Ahsan, and Hassan A. Alhazmi Copyright © 2017 Neelaveni Thangavel et al. All rights reserved. Biophysical Approaches Facilitate Computational Drug Discovery for ATP-Binding Cassette Proteins Sun, 19 Mar 2017 00:00:00 +0000 Although membrane proteins represent most therapeutically relevant drug targets, the availability of atomic resolution structures for this class of proteins has been limited. Structural characterization has been hampered by the biophysical nature of these polytopic transporters, receptors, and channels, and recent innovations to in vitro techniques aim to mitigate these challenges. One such class of membrane proteins, the ATP-binding cassette (ABC) superfamily, are broadly expressed throughout the human body, required for normal physiology and disease-causing when mutated, yet lacks sufficient structural representation in the Protein Data Bank. However, recent improvements to biophysical techniques (e.g., cryo-electron microscopy) have allowed for previously “hard-to-study” ABC proteins to be characterized at high resolution, providing insight into molecular mechanisms-of-action as well as revealing novel druggable sites for therapy design. These new advances provide ample opportunity for computational methods (e.g., virtual screening, molecular dynamics simulations, and structure-based drug design) to catalyze the discovery of novel small molecule therapeutics that can be easily translated from computer to bench and subsequently to the patient’s bedside. In this review, we explore the utility of recent advances in biophysical methods coupled with well-established in silico techniques towards drug development for diseases caused by dysfunctional ABC proteins. Steven V. Molinski, Zoltán Bozóky, Surtaj H. Iram, and Saumel Ahmadi Copyright © 2017 Steven V. Molinski et al. All rights reserved. Benzyl-1,2,4-triazoles as CB1 Cannabinoid Receptor Ligands: Preparation and In Vitro Pharmacological Evaluation Thu, 31 Mar 2016 13:03:53 +0000 In a previous study, we have identified 3-alkyl-1,5-diaryl-1H-1,2,4-triazoles to be a novel class of cannabinoid type 1 receptor (CB1R) antagonists. In order to expand the number of cannabinoid ligands with a central 1,2,4-triazole scaffold, we have synthesized a novel series of 1-benzyl-1H-1,2,4-triazoles, and some of them were evaluated by CB1R radioligand binding assays. Compound 12a showed the most interesting pharmacological properties, possessing a CB1R affinity in the nanomolar range. Laura Hernandez-Folgado, Juan Decara, Fernando Rodríguez de Fonseca, Pilar Goya, and Nadine Jagerovic Copyright © 2016 Laura Hernandez-Folgado et al. All rights reserved. ct-DNA Binding and Antibacterial Activity of Octahedral Titanium (IV) Heteroleptic (Benzoylacetone and Hydroxamic Acids) Complexes Wed, 16 Mar 2016 14:12:01 +0000 Five structurally related titanium (IV) heteroleptic complexes, [TiCl2(bzac)(L1–4)] and [TiCl3(bzac)(HL5)]; bzac = benzoylacetonate; L1–5 = benzohydroximate (L1), salicylhydroximate (L2), acetohydroximate (L3), hydroxyurea (L4), and N-benzoyl-N-phenyl hydroxylamine (L5), were used for the assessment of their antibacterial activities against ten pathogenic bacterial strains. The titanium (IV) complexes (1–5) demonstrated significant level of antibacterial properties as measured using agar well diffusion method. UV-Vis absorption spectroscopic technique was applied, to get a better insight into the nature of binding between titanium (IV) complexes with calf thymus DNA (ct-DNA). On the basis of the results of UV-Vis absorption spectroscopy, the interaction between ct-DNA and the titanium (IV) complexes is likely to occur through the same mode. Results indicated that titanium (IV) complex can bind to calf thymus DNA (ct-DNA) via an intercalative mode. The intrinsic binding constant () was calculated by absorption spectra by using Benesi-Hildebrand equation. Further, Gibbs free energy was also calculated for all the complexes. Raj Kaushal, Sheetal Thakur, and Kiran Nehra Copyright © 2016 Raj Kaushal et al. All rights reserved. New Conjugates of Quinoxaline as Potent Antitubercular and Antibacterial Agents Tue, 08 Mar 2016 12:44:07 +0000 Considering quinoxaline as a privileged structure for the design of potent intercalating agents, some new sugar conjugates of quinoxaline were synthesized and characterized by IR, 1HNMR, 13C NMR, and mass spectral data. In vitro testing for antitubercular and antimicrobial activities was performed against Mycobacterium tuberculosis H37Rv and some pathogenic bacteria. Results revealed that conjugate containing ribose moiety demonstrated the most promising activity against Mycobacteria and bacteria with minimum inhibitory concentrations (MIC) of 0.65 and 2.07 μM, respectively. Other conjugates from xylose, glucose, and mannose were moderately active whilst disaccharides conjugates were found to be less active. In silico docking analysis of prototype compound revealed that ATP site of DNA gyrase B subunit could be a possible site for inhibitory action of these synthesized compounds. Ramalingam Peraman, Rajendran Kuppusamy, Sunil Kumar Killi, and Y. Padmanabha Reddy Copyright © 2016 Ramalingam Peraman et al. All rights reserved. Changes in the Physicochemical Properties of Piperine/β-Cyclodextrin due to the Formation of Inclusion Complexes Mon, 22 Feb 2016 16:44:01 +0000 Piperine (PP) is a pungent component in black pepper that possesses useful biological activities; however it is practically insoluble in water. The aim of the current study was to prepare a coground mixture (GM) of PP and β-cyclodextrin (βCD) (molar ratio of PP/βCD = 1/1) and subsequently evaluate the solubility of PP and physicochemical properties of the GM. DSC thermal behavior of the GM showed the absence of melting peak of piperine. PXRD profile of the GM exhibited halo pattern and no characteristic peaks due to PP and βCD were observed. Based on Job’s plot, the PP/βCD complex in solution had a stoichiometric ratio of 1/1. Raman spectrum of the GM revealed scattering peaks assigned for the benzene ring (C=C), the methylene groups (CH2), and ether groups (C-O-C) of PP that were broaden and shifted to lower frequencies. SEM micrographs showed that particles in the GM were agglomerated and had rough surface, unlike pure PP and pure βCD particles. At 15 min of dissolution testing, the amount dissolved of PP in the GM was dramatically increased (about 16 times) compared to that of pure PP. Moreover the interaction between PP and βCD cavity was detected by 1H-1H NMR nuclear Overhauser effect spectroscopy NMR spectroscopy. Toshinari Ezawa, Yutaka Inoue, Sujimon Tunvichien, Rina Suzuki, and Ikuo Kanamoto Copyright © 2016 Toshinari Ezawa et al. All rights reserved. Design and Microwave Assisted Synthesis of Coumarin Derivatives as PDE Inhibitors Sun, 21 Feb 2016 11:48:04 +0000 Coumarins appended to benzimidazole through pyrazole are designed and synthesized using microwave irradiation. These compounds were analyzed for phosphodiesterase (PDE) inhibition indirectly by motility pattern in human spermatozoa. Some of the synthesized compounds, namely, 5d, 5e, 5f, 5g, 5h, and 5k, have exhibited potent inhibitory activity on PDE. Mahadev N. Kumbar, Ravindra R. Kamble, Atulkumar A. Kamble, Sujith Raj Salian, Sandhya Kumari, Ramya Nair, Guruprasad Kalthur, Satish Kumar Adiga, and D. Jagadeesh Prasad Copyright © 2016 Mahadev N. Kumbar et al. All rights reserved. Biological Impact of Pd (II) Complexes: Synthesis, Spectral Characterization, In Vitro Anticancer, CT-DNA Binding, and Antioxidant Activities Tue, 16 Feb 2016 12:38:02 +0000 A new series of Pd (II) complexes of methyl substituted benzylamine ligands (BLs) has been synthesized and characterized via spectroscopic techniques such as UV/Vis. FTIR, LCMS, 1H, and 13C NMR. The UV/Vis study in DMSO, DMSO + water, and DMSO + PBS buffer (pH = 7.2) confirmed their molecular sustainability in liquids. Their in vitro anticancer activity against breast cancer cell lines such as MCF-7 and MDA-MB-231 makes them interesting for in vivo analysis. Their stronger DNA binding activity (DBA) compared with free ligand suggested them as a good DNA binder. DBA was further confirmed by physicochemical studies such as surface tension and viscosity of complex + DNA which inferred the disruption of DNA and intercalation of complexes, respectively. Their % binding activity, % disruption of DNA base pairs (DNABP), and % intercalating strength are reported in this paper for the first time for better understanding of DNA binding mechanism. Along with this, their scavenging activity (SA) determined through DPPH free radical and the results indicate good antioxidant behaviour of complexes. Nitin Kumar Sharma, Rakesh Kumar Ameta, and Man Singh Copyright © 2016 Nitin Kumar Sharma et al. All rights reserved. Synthesis, In Vivo Anti-Inflammatory Activity, and Molecular Docking Studies of New Isatin Derivatives Sun, 14 Feb 2016 11:41:11 +0000 A novel synthesis of 2-hydroxy-N′-(2-oxoindolin-3-ylidene) benzohydrazide derivatives was synthesized by the condensation of 2-hydroxybenzohydrazide with substituted isatins. The synthesized compounds were characterized by FT-IR, 1H-NMR, and mass spectral data. Further, the compounds were screened for in vivo anti-inflammatory activity by carrageenan induced paw edema method. The tested compounds have shown mild-to-moderate anti-inflammatory activity. The compounds VIIc and VIId exhibited 65% and 63% of paw edema reduction, respectively. The molecular docking studies were also carried out into the active site of COX-1 and COX-2 enzymes (PDB ID: 3N8Y, 3LN1, resp.) using VLife MDS 4.3. The compounds VIIc, VIId, and VIIf exhibited good docking scores of −57.27, −62.02, and −58.18 onto the active site of COX-2 and least dock scores of −8.03, −9.17, and −8.94 on COX-1 enzymes and were comparable with standard COX-2 inhibitor celecoxib. A significant correlation was observed between the in silico and the in vivo studies. The anti-inflammatory and docking results highlight the fact that the synthesized compounds VIIc, VIId, and VIIf could be considered as possible hit as therapeutic agents. Ravi Jarapula, Kiran Gangarapu, Sarangapani Manda, and Sriram Rekulapally Copyright © 2016 Ravi Jarapula et al. All rights reserved. Syntheses and Antibiotic Evaluation of 2-[(2R,4R)-4-Carboxy-2-hydroxypyrrolidin-1-yl]carbonylbenzene-1,5-dicarboxylic Acids and 2-Carbamoylbenzene-1,5-dicarboxylic Acid Analogues Sun, 14 Feb 2016 06:05:04 +0000 Our search for new antibiotics led to the syntheses and biological evaluation of new classes of dicarboxylic acid analogues. The syntheses involve nucleophilic addition of different substituted benzylamine, aniline, alkylamine, and 4-hydroxyl-L-proline with carbamoylbenzoic acid. The results of the antimicrobial activity as indicated by the zone of inhibition (ZOI) showed that Z10 is the most active against Pseudomonas aeruginosa (32 mm) and least active against Candida stellatoidea (27 mm) and Vancomycin Resistant Enterococci (VRE) (27 mm), while Z7 shows the least zone of inhibition (22 mm) against Methicillin Resistant Staphylococcus aureus (MRSA). The minimum inhibition concentration (MIC) determination reveals that Z10 inhibits the growth of tested microbes at a low concentration of 6.25 μg/mL, while Z9 and Z12 inhibits the growth of most microbes at a concentration of 12.5 μg/mL, recording the least MIC. The Minimum Bactericidal/Fungicidal Concentration (MBC/MFC) results revealed that Z10 has the highest bactericidal/fungicidal effect on the test microbes, at a concentration of 12.5 μg/mL, with the exception of Candida stellatoidea and Vancomycin Resistant Enterococci (VRE) with MBC/MFC of 25 μg/mL. The result of this investigation reveals the potential of the target compounds (Z1–3,5,7–12) in the search for new antimicrobial agents. Abdulrazaq Tukur, Isaac Asusheyi Bello, Neil Anthony Koorbanally, and James Dama Habila Copyright © 2016 Abdulrazaq Tukur et al. All rights reserved. Synthesis and Evaluation of Mannitol-Based Inhibitors for Lipopolysaccharide Biosynthesis Thu, 11 Feb 2016 11:40:16 +0000 Antibiotic resistance is a serious threat against humankind and the need for new therapeutics is crucial. Without working antibiotics, diseases that we thought were extinct will come back. In this paper two new mannitol bisphosphate analogs, 1,6-dideoxy-1,6-diphosphoramidate mannitol and 1,6-dideoxy-1,6-dimethansulfonamide mannitol, have been synthesized and evaluated as potential inhibitors of the enzyme GmhB in the biosynthesis of lipopolysaccharides. 1,6-Dideoxy-1,6-diphosphoramidate mannitol showed promising result in computational docking experiments, but neither phosphate analog showed activity in the Kirby-Bauer antibiotic susceptibility test. Richard E. Johnsson Copyright © 2016 Richard E. Johnsson. 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.