New benzimidazole derivatives as inhibitors of Pteridine reductase 1: Design, molecular docking study and ADMET prediction

Pteridine reductase 1 (PTR1) is a unique enzyme required for survival of Leishmania species, a causative organism forthe disease leishmaniasis. We herein report the design, docking, and Absorption, Distribution, Metabolism, Excretion,Toxicity (ADMET) prediction studies of 2-substituted-5-[(6-substituted-1H-benzimidazol-2yl)methyl]azole derivatives(B1–B14) as PTR1 inhibitors. Molecular docking studies showed good binding interaction of the compounds withthe active site of pteridine reductase from Leishmania Major, with compounds B5 and B12 showing docking scoresof −61.5232 and −62.5897, respectively, which were comparable with the original ligand, dihydrobiopterin. Largesubstituents on the azole ring, as well as substitutions on sixth position of the benzimidazole ring, were found to befavorable for interaction with PTR1 active site. Physicochemical properties, bioactivity prediction, and toxicity profilesof the compounds were studied using the Molinspiration and admetSAR web servers. All compounds followed Lipinski’srule of five and can be considered as good oral candidates. Bioactivity prediction indicated that the compounds wereenzyme inhibitor, thus the rationale for designing PTR1 inhibitors was met. Most of the compounds were predicted tohave good ADMET properties in terms of Gastrointestinal (GI) absorption, absence of P-glycoprotein interaction, andLD50 values in rats. The designed molecules can be further explored for their antileishmanial activity

Molecular Docking Studies Of Hgv-6 Analogue As A Potential Pbp-1a Inhibitor

Objective: The sygnificance of this study is to find a new hexagamavunon-6 analogue (HGV-6); 3,5-bis-(4´-chlorobenzylidene)-tetrahydro-4H-thiopyran-4-one (D144); 3,5-bis-(2´,4´-dichlorobenzylidene)-tetrahydro-4H-thiopyran-4-one (D154); 3,5-bis-(3´,5´-dichlor ro-4´-hydroxybenzylidene)-tetrahydro-4H-thiopyran-4-one (D156) as a potential PBP-1A inhibitor. Methods: Docking method through Molecular Operating Environment (MOE) software was used to design a new HGV-6 analogue and study its interaction with penicillin binding protein (PBP-1a). This docking study used parameterized model 3 (PM3) method through Polak Ribiere algorithm to calculate the optimal structural geometry of the compound. Protein validation was carried out to ensure that the protein was suitable for use. Results: The results of the docking study show that the docking scores of D144 (-9.7942) and D154 (-10.1961) are higher than D156 (-12.2604), while D156 is lower than HGV-6 (-11.7958). Ampicillin (-13.6496) as a native ligand has the smallest docking score compared to the test compounds. Conclusion: The results of the docking study show that 3,5-bis-(3,5-dichloro-4-hydroxybenzylidene)-tetrahydro-4H-thiopyran-4-one (D156) has a better potential antibacterial compound than HGV-6.

Synthesis Characterization And Antimicrobial Activities Studies Of N-{2-(4-Chlorophenyl) Acetyl} Amino Alcohols Derived From Α-Amino Acids

Amino acids play important roles in organisms to sustain in living state and perform as body constituents, enzymes and antibodies. At insalubrious situations, use of amino acids derivatives as drugs in the maintenance of normal health is better choice than common unnatural synthetic drugs. This is due to the fact that the amino acids derivatives may be more bio-compatible, biodegradable and eliminate easily than others. In this sense we have made an effort and report herein the synthesis of N-{2-(4-chlorophenyl) acetyl} amino alcohols synthesised by reduction of N-{2-(4-chlorophenyl)acetyl} derivatives of (S)-amino acids such as (S)-phenylalanine, (S)-alanine, (S)-methionine, (S)-leucine, (S)-tryptophan and (S)-proline. These newly synthesized amino acids derivatives were analysed by proton, carbon-13 NMR and FT-IR spectroscopy. The composition of solid derivatives was determined by elemental analysis. Further, antimicrobial activities of these derivatives were assessed on usual bacteria K. aerogenes, E. coli, S. aureus and P. desmolyticum and fungi A. flavus and C. albicans. The compounds were witnessed moderate activity than authorised antibacterial and fungal agents Ciprofloxacin and Fluconazole respectively. The antimicrobial studies also revealed that, these derivatives could be better antifungal agents than antibacterial agents. Finally we compared the experimental results of antimicrobial activities with docking studies.

1, 3, 4-Thiadiazole and 1, 2, 4-triazole-3(4 H )-thione bearing salicylate moiety: synthesis and evaluation as anti- Candida albicans

Abstract Dramatically increased occurrence of both superficial and invasive fungal infections has been observed. Candida albicans appear to be the main etiological agent of invasive fungal infections. The anti-C. albicans activity of thiosemicarbazide, 1,3,4-Thiadiazole, and 1,2,4-triazole-3(4H)-thione compounds (compounds 3-23) were investigated. The MIC values of thiadiazole and triazole derivatives 10-23 were in the range of 0.08-0.17 µmol mL-1, while that of fluconazole was 0.052 µmol mL-1. Compound 11 (5-(2-(4-chlorobenzyloxy)phenyl)-N-allyl-1,3,4-thiadiazol-2-amine) and compound 18 (5-(2-(4-chlorobenzyloxy)phenyl)-4-allyl-2H-1,2,4-triazole-3(4H)-thione) were found to be the most active compounds, with MIC values of 0.08 µmol mL-1. The newly synthesized thiadiazole and triazole compounds (compounds 10-23) showed promising anti-Candida activity. The allyl substituent-bearing compounds 11 and 18 exhibited significant anti-Candida albicans activity and showed a binding mode as well as the fluconazole x-ray structure.

2,3-Diaryl-3-imidazo4,5-pyridine derivatives as potential anticancer and anti-inflammatory agents

In this study we examined the suitability of the-imidazo[4,5-]pyridine ring system in developing novel anticancer and anti-inflammatory agents incorporating a diaryl pharmacophore. Eight 2,3-diaryl-3-imidazo[4,5-]pyridine derivatives retrieved from our in-house database were evaluated for their cytotoxic activity against nine cancer cell lines. The results indicated that the compounds showed moderate cytotoxic activity against MCF-7, MDA-MB-468, K562 and SaOS2 cells, with K562 being the most sensitive among the four cancer cell lines. The eight 2,3-diaryl-3-imidazo[4,5-]pyridine derivatives were also evaluated for their COX-1 and COX-2 inhibitory activity. The results showed that compoundexhibited 2-fold selectivity with ICvalues of 9.2 and 21.8 µmol/L against COX-2 and COX-1, respectively. Molecular docking studies on the most active compoundrevealed a binding mode similar to that of celecoxib in the active site of the COX-2 enzyme.

Mechanism of Relaxant Action of Ethyl 6-amino-5-cyano-2-methyl- 4-(pyridin-4-yl)-4H-pyran-3-carboxylate Mainly Through Calcium Channel Blockade in Isolated Rat Trachea.

This study aims to investigate the mechanism of relaxant action of Ethyl 6-amino-5-cyano-2-methyl-4-(pyridin- 4-yl)- 4H-pyran-3-carboxylate (1) in in silico study and ex vivo tracheal rat rings pre-contracted with carbachol (1 µM). Compound 1 was more active than theophylline [a phosphodiesterases (PDE’s) inhibitor] used as positive control. Moreover, pretreatment with 1 significantly shifted to the right the carbachol-induced contraction and did not allow to reach the maximum effect (p< 0.001). In addition, compound 1 (96.30 µM) produces significant (100%) relaxant effect on the contraction induced by KCl (80mM), and the CaCl2-induced contraction was completely abolished by 1 as nifedipine does (a L-type calcium channel blocker), used as positive control (p< 0.001). Meanwhile, in the presence of isoproterenol (a β-adrenergic agonist), propranolol (a β-adrenergic antagonist), and K+ channel blocker 2-AP the relaxant curve was significantly modified (p< 0.05). Compound 1 was docked on an outer cavity located on the intracellular side of the human L-type calcium channel model and interacts in the following chains and residues: chain IP (G51, W52, T53, D54), IVP (R45, E50, A51, Q53, D54) and IS6 (W4, F7). In conclusion, ex vivo and in silico approaches suggest that compound 1 induces its relaxant effect mainly by calcium channel blockade, but other mechanisms like potassium channel and cAMP accumulation could be involved.

An In-Silico Evaluation of Some Novel Curcumin Derivatives for Antibacterial Activity Against Methicillin Resistant Staphylococcus Aureus.

The multiple drug resistance in MRSA (Methicillin resistant Staphylococcus aureus) has become a major clinical problem worldwide. Methicillin resistance (mediated by PBP2a protein) is a serious issue limiting treatment options and necessitating the search of newer safe and effective alternative treatment regimens. Aim of the present study was to evaluate the potential of the plant product ‘Curcumin’ and its derivatives as effective antibacterial agents by means of insilico based studies. Computer aided drug designing is an initial platform helpful to screen novel inhibitors and has tremendous application in the development of new drugs. In the present study a series of 16 derivatives of curcumin were constructed and optimized using chemsketch software.Molecular docking was performed using the GOLD (Genetic Optimization of Ligand Docking) software which is based on genetic algorithm (GA), to study the binding orientation of these derivatives into the PBP2a structure. Derivative 10 (1E,6E)-1,7-bis(3- hydroperoxy-4-hydroxyphenyl)hepta-1,6-diene-3,5-dione) showed best docking fitness value compared to other derivatives(including Curcumin). The molecular, physicochemical, and biological properties were calculated (through molinspiration cheminformatics software) for compounds showing the best docking scores. These compounds were further subjected to toxicity predictions using the Osiris software.

Anti-uropathogenic activity, drug likeness, physicochemical and molecular docking assessment of (E-)-N0-(substituted-benzylidene)-2-(quinolin-8-yloxy) acetohydrazide

Objective: To deal with the anti-uropathogenic and in silico screening of (E-)-N'- (substituted-benzylidene)-2-(quinolin-8-yloxy)acetohydrazide analogues in order to search the potential anti-uropathogenic agents. Methods: Three (E-)-N'-(substituted-benzylidene)-2-(quinolin-8-yloxy)acetohydrazide analogues were synthesized. Structure elucidation was done using various spectroscopic techniques including infrared radiation, 1hydrogen-nuclear magnetic resonance, carbon- 13 nuclear magnetic resonance, etc. Physicochemical score, bioactivity score and molecular docking studies were carried out using Lipinski's rule of five, Molinspiration (web based software), Autodock 4.2 tools. In vitro anti-uropathogenic activity was carried out against four pathogens named as Staphylococcus aureus (S. aureus), Staphylococcus epidermidis, Proteus mirabilis and Escherichia coli by disc diffusion method and macrodilution test following their morphological and biochemical characterization. Results: The formation of (E-)-N'-(substituted-benzylidene)-2-(quinolin-8-yloxy)acetohydrazide is confirmed from the spectroscopic results. All the compounds were found in compliance with Lipinski's rule of five and exhibited bioactivity score from -0.50 to 0.00. Docking results revealed that compound-1 is forming one hydrogen bond with TYR 576 and two hydrogen bond with GLU 569, while compound-2 is forming one hydrogen bond with ARG 599, and compound-3 forming 0 hydrogen bond. The anti-uropathogenic evaluation exhibited that compound one exhibited better activity against S. aureus, while it was found to possess moderate to good activity against both Gram-positive bacteria and Gram-negative bacteria excluding S. aureus. Conclusions: Our study revealed that compound one exhibited better activity than the standard in case of S. aureus and moderate to good activity against rest of the pathogens. Molecular docking, physicochemical and bioactivity studies strongly supported the experimental results. From the well obtained results it was concluded that compound-1 can lead as potential anti-uropathogenic agents.

Molecular p prediction, docking studies and synthesis of 5-benzimidazole-1-Yl-methyl –[1,3,4] oxadiazole-2-thiol and their derivatives.

Molecular property is a complex balance of various structural features which determine whether a particular molecule is similar to the known drugs.These properties mainly hydrophobicity, molecular size,flexibility and presence of various pharmacophoric features influence the behavior of molecules in a living organism, including oral bioavailability. This investigation deals with the design and calculation of molecular properties, drug likeness, lipophilicity and solubility parameters of 5-Benzimidazole-1-yl-methyl-[1, 3, 4] oxadiazole-2-thiol and their derivatives using Osiris, mol inspiration ,Mol soft software’s, and ALOPGPS 2.1 program. The compounds followed the Lipinski ‘Rule of five’ for better bioavailability, were synthesized and characterized by IR, NMR, and mass spectral analysis. Furthermore, the binding conformations of these compounds for anti inflammatory activities were determined in silico docking. This is an energy optimization process concerned with the search of the lowest free energy binding mode of a ligand within a protein binding site and estimates the forces involved in the protein-ligand recognition, carried out in Mastro V 2011 in the active site of the cyclooxygenase-2 (COX-2) enzyme.