Argus Lab Research Articles

Green synthesis, molecular structure, spectroscopic, ADME, DFT and molecular docking studies on methyl 10-trans,12-cis-octadecadienoate

The methyl 10-trans, 12-cis-octadecadienoate (MOD) obtained from the methanol extract of Calotropis gigantea flowers was studied using spectroscopic, computational molecular modelling and DFT methods in the current work. The Calotropis gigantea flowers were collected from the surroundings of Tamil Nadu, India's Thiruvallur district. The preparation for extraction of bioactive compound from Plant - based green synthesis of MOD from Calatropis gigantea. The FTIR spectra of MOD have been measured between in 400 and 4000 cm−1. Density functional theory is employed to determine the geometry of the molecules, vibrational frequencies and geometrical parameters by using B3LYP/6–311++G (d, p) basis set. The identification of the modes of vibration depended on the potential energy distributions (PEDs) which have been computed. The HOMO-LUMO energies, chemical hardness, and electro negativity of the molecule have been determined via the DFT/B3LYP/6–311++G (d, p) method. The intra molecular interactions and hydrogen bonding have been interpreted using natural bond orbital analysis by NBO 3.1 program. UV–Visible absorption spectra in the wavelength range of 200–400 nm was noticed, which indicates a molecular exchange of charges inside the molecule. The time dependent density functional theory (TD-DFT) method adopted for this study to determine the excited states of the title molecule. The Argus Lab application was implemented to evaluate the molecular docking tests that were conducted to look at the anti-cancer capabilities of the MOD molecule against Caspase 3.

Synthesis, Cannabinoid Receptor Targeted Molecular Docking of Some New Pyrazole Derivatives as Hypolipidemic and Anti- Obesity Agents

Obesity is a serious health problem of 21st century. Around 1 billion adults are overweight and more than 300 million people are found to be obese globally. In fact 2.6 million people die per year due to obesity and thus it has now become a major reason of morbidity and mortality. In line to this few novel pyrazole derivatives (Z)-3-(4-subtituted phenyl)-2-(3, 5-dimethyl-1H-pyrazol-1-yl)-1-phenylprop-2-en-1-one (4a-f) were synthesized from 3, 5 dimethyl pyrazole by a simple inexpensive, rapid method. All compounds were authenticated using different physical and analytical techniques such as Infrared, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance and mass spectrometry. Hypolipidemic activity was carried out for all the compounds using Triton WR 1339 induced hyperlipidemia model in rodents. Further, molecular docking was performed to understand the receptor-ligand interactions of synthesized compounds with cannabinoid receptor (protein data bank code: 5TGZ) using Argus lab 4.0, followed by anti-obesity studies of the selected compound (Z)-3-(4-chlorophenyl)-2-(3, 5-dimethyl-1H-pyrazol-1-yl)-1-phenylprop-2-en-1-one (4b). Amongst six compounds four compounds showed significant reduction in cholesterol levels in along with triglyceride levels in hyperlipidemic rats. Compound 4b also caused significant elevation in % high density lipoprotein levels of rats comparable to the standard Gemfibrozil. All these compounds showed good interactions with the target protein. Compound 4b (5 mg/kg and 10 mg/kg orally), caused notable reduction in body weight of high fat diet rats. Compound 4b i.e. (Z)-3-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1- yl)-1-phenylprop-2-en-1-one has ability to reduce body weight and improve lipid profile in rats and requires further studies to establish its safety and efficacy in preclinical and clinical subjects.

IDENTIFICATION OF NOVEL DRUG/LEAD MOLECULE FOR SCHIZOPHRENIA TARGETING RGS4 GENE THROUGH IN-SILICO ANALYSIS

Schizophrenia is a neuropsychiatric disorder that is caused by many factors including changes in the chemistry of the brain, structure of the brain, and genetic factors. The neuropathology of the disorder has been identified morphologically and physiologically through a number of parameters from a reduction in brain size and abnormalities in the neurotransmitter network affecting the brain to changes in the molecular composition of specific cell populations in the brain. Over a long period of time, clinicians and researchers have identified schizophrenia as a complex neurological genetic disorder as a result of the functionality of several susceptible genes. Various scientists are of the opinion that there are about 20 candidate genes that cause schizophrenia. Several genes like Dysbindin, Neuregulin, DAAO, G72, PRODH, COMT, and RGS4 have been proven to be the risk factors for schizophrenia disease. RGS4 was identified as a target gene for schizophrenia. Hence the present study was taken up to identify a Novel Drug/Lead Molecule from 12 selected drugs based on a bioinformatics approach for schizophrenia targeting the RGS4 gene. The genomics and proteomics approach of the RGS4 gene was carried out for nucleotide and protein sequences and the protein was modeled using SPDBV with 80% accuracy. The potential active site amino acids were predicted using molecular cavities based on energy and surface area and the protein was targeted using the best active site amino acids. The protein-ligand interactions were also performed using the Argus Lab engine with flexible docking. The data of the present study reveals that ziprasidone is showing maximum inhibition of the RGS4 gene among the 12 drugs selected for screening. It is thus concluded that ziprasidone with the lowest free energy and high affinity is the best inhibitor for the schizophrenia protein and hence it can be suggested for the treatment of schizophrenia.

Molecular Docking studies of THC-HCA on Cancer Receptors

Cancer is a group of diseases which involves abnormal cell growth that can spread to other parts of the body. There are certain characteristics that are required to produce a malignant tumour. They include: Avoidance of programmed cell death and uncontrolled cell division to name a few. The progression from normal cells to cells that can form a detectable mass to outright cancer involves multiple steps known as malignant progression. Cannabinoids are among the treatment available. Recent research has shown that cannabinoid coupled with hydroxy citric acid can be used in the treatment of melanoma. Hydroxy citric acid is a derivative of citric acid well known for its anti-obesity and anti-inflammatory property. The current project involves the coupling of tetrahydrocannabinol with hydroxy citric acid to develop a novel drug molecule for potential cancer treatment. Simulation tool like Argus lab is used to construct the 3D structure of the novel drug. Autodock was used to bind the drug with the receptors like TRPV1, CB1, CB2, 4QO1 and 2YGB.

Molecular docking for rationalizing the use of linkers in polymer drug conjugates design for pegylated anti-inflammatory drug delivery

A smart linker is a crucial element throughout the creation of polymer-drug conjugates. It binds different portions or subunits altogether and may be freed by a suitable trigger, resulting in localized drug distribution and enhanced bioavailability. PEG (Polyethylene Glycol) linkers can be synthesized chemically by specifically adding functionalized groups with chemical reactivity at certain structural ends of PEG. Because they may integrate a diverse range of groups, PEG linkers are frequently utilized in molecular biology experiments due to increased water solubility, excellent biocompatibility, and non-immunogenicity. In present work, we have included various linkers which are incorporated in design of PDC’s (polymer drug conjugates) of pegylated NSAIDs (nonsteroidal anti-inflammatory drugs) through PEGylation. The main focus was to investigate the pharmacodynamic changes brought about by these linker’s conjugated to model drug Ibuprofen (IB1-IB7). The tools used for the analysis are Argus Lab 4.0 for molecular docking and pkCMS as ADMET prediction tool. The outcome of this work was, establishment of a method for choosing suitable linker for designing PDC’s for various NSAIDs and other bioactive agents.

Synthesis, structural investigation and molecular docking studies of pyridinyl tetrahydroisoquinoline, morpholine and piperidine containing schiff's bases

The present work was conducted to synthesize some Schiff's bases derived from pyridinyl tetrahydroisoquinoline, morpholine and piperidine moieties by the condensation reaction of aminobenzaldehyde with various aromatic amines in good to excellent yield. The structures of synthesized compounds were confirmed by 1H NMR, 13C NMR and mass spectra (ESI-MS) data. These compounds also evaluated for their in silico anti-microbial properties by molecular docking studies. Docking studies were carried out by using Argus Lab 4.0.1 software.

Alcohol exacerbated biochemical and biophysical alterations in liver mitochondrial membrane of diabetic male wistar rats – A possible amelioration by green tea

Alcohol exacerbated biochemical and biophysical alterations in liver mitochondrial membrane of diabetic male wistar rats – A possible amelioration by green tea

Molecular Docking Study of Alzheimer Disease Responsible Protein Inhibition Activity by Bioactive Ginkgolides

Terpenoids are major components present in herbal formulations of Ginkgo biloba which are considered to slow down progression of Alzheimer disease. Ginkgolide A, Ginkgolide B, Ginkgolide C, Ginkgolide M, Ginkgolide J, Ginkgolide K and Bilobalide are some of the terpenoids selected for computational theoretical calculations using DFT theory at B3LYP/6-311+G*(d,p) basic set level using Gaussian 16W. To study the interaction between selected terpenoids and selected proteins, molecular docking analysis is carried out using Argus Lab (4.0.1) and Auto Dock (4.2). Calculations are carried out on efficient shape-based search algorithm principle and a score base function to calculate the binding energies between them. ADMET analysis provide properties insight of terpenoids compounds. Results from calculated data reveal that there are possible interactions. This data can help in development of potent protein kinase inhibitor for the treatment of Alzheimer.

Comparative molecular docking studies of phytochemicals as Jak2 inhibitors using Autodock and ArgusLab

Cancer is one of the major threats that we face today due to the lack of a proper medicine and its harmful side effects. JAK- STAT pathway has been reported to involve in oncogenesis. Molecules with known JAK2 inhibitory activity were subjected to docking to JAK2 protein using Autodock and Argus lab softwares. The difference in binding energy obtained from both the softwares is due to the difference in parameters used in binding energy calculation. The results show that Autodock outperforms largely ArgusLab in the binding energy correlation with the biological activity. Phytochemicals having anticancer property retrieved from Dr Dukes phytochemical and ethnobotanical database were then docked using Autodock. The phytochemical ajmalimine was identified to have high affinity to the target protein which can be modified to get potent novel JAK2 inhibitors.

Relationship between Molecular Structure and Relative Sweetness of Various Artificial Sweeteners.

In the present work, the relationship between the molecular properties and sweetness level of a number of artificial sweeteners like aspartame, neotame, saccharin, sucralose, cyclamate, xylitol and alitame was studied. The molecular structures of the artificial sweeteners were generated, optimized and their properties like electrostatic potential, dipole, heat of formation, HOMO (Highest Occupied Molecular Orbital) and LUMO (Lowest Unoccupied Molecular Orbital) were calculated using Argus lab. Further, identification of AH, B and X sites based on AH-B-X theory was done with the help of electrostatic potential mapping, HOMOs and LUMOs for a few artificial sweeteners. A comparison was done among the sweeteners between their relative sweetness values by considering their structures and the way in which sugars bond to receptor sites. An attempt was made to develop a relationship between the relative sweetness and molecular properties of the sweeteners.

Antifebrin Drug Prepared via One-Stage Green Method as Sustainable Corrosion Inhibitor for Al in 3 M HCl Medium: Insight from Electrochemical, Gasometric, and Quantum Chemical Studies

The medicinal compound antifebrin was prepared in the laboratory via one stage (green method) by using aniline, glacial acetic acid, and zinc dust. The investigation was aimed at ascertain a possibility of utilizing the medicinal compound to originate a corrosion inhibitor for Al in a 3 M HCl solution. In the present article, the usefulness of antifebrin to inhibit the Al corrosion in 3 M HCl solution was examined by the Tafel plot, AC impedance spectroscopy, gasometric and quantum chemical techniques. The Tafel plot results show that concentration of antifebrin has a positive effect on the inhibition efficiency. The Tafel plot also reveals that this medicinal compound inhibits the acidic corrosion of aluminum by a mixed mode. Impedance spectroscopy results show that corrosion resistance of Al in a 3 M hydrochloric acid was improved by antifebrin. For better understanding the relationship between the antifebrin molecular structure and inhibitory ability, quantum calculations (by using Argus Lab = latest version) were performed. Surface studies were carried out by scanning electron microscopy. The Langmuir plot confirms the chemical adsorption mechanism on the Al surface in a 3 M HCl solution in the presence of antifebrin.

Frankincense essential oil extraction and lead compound analysis into cancer cells using molecular docking

Oil was extracted from Frankincense (Boswellia Sacra) by the soxhlet extraction method and various bioactive compounds were identified using gas chromatography (GC).These compounds can be developed as active pharmacophores.The present study involves the extraction and identification of bioactive compounds and their in-vitro study on the interaction of these compounds to target proteins. Frankincense oil collected from Boswelia Sacra species was subjected to Soxhlet extraction using Hexane solvent and essential oil (EO) was separated using vacuum distillation. Chemical profiling of essential oil was done using GC-MS. Various biological databases like PubChem, Protein Data Bank and software like Argus Lab, Rasmol were used to retrieve and analyze the structural and molecular interactions of bioactive compounds from Frankincense oil with receptor proteins. The target protein structure was retrieved from Protein data bank ligand structures that were downloaded from Pubchem, which was visualized using Rasmol Software. Protein-ligand interaction was studied using Argus Lab software by docking simulations and various docking poses were analyzed.The energy values of docking conformations were analyzed for obtaining the best docking pose & score.

MICROWAVE ASSISTED SYNTHESIS OF TETRAHYDROPYRMIDINE AND IN SILICO SCREENING OF ANTIDIABETIC DRUG

Objective: To detect the microwave-assisted synthesis of Tetrahydropyrimidine derivative and its molecular docking studies for Diabetes.
 Methods: The Bignelli condensation method was used for Tetrahydropyrimidine derivative synthesis. The docking studies made in Argus Lab software.
 Results: The Tetrahydropyrimidine is synthesized using the microwave. The Tetrahydropyrimidine derivative is found to be attack the insulin receptor, as it the tendency of binding with insulin receptor showed in Argus lab. Further, the good binding site of Tetrahydropyrimidine derivative with insulin receptor was predicted.
 Conclusion: From the research work, The Tetrahydropyrimidine derivative shows its affinity to bind with the insulin receptor. The binding value is averagely 7 which indicates it can attraction with the receptor, so it can control Diabetic mellitus by altering insulin secretion in blood plasma.

Structural Elucidation, 3D Molecular Modeling and Antibacterial Activity of Ni (II), Co (II), Cu (II) and Mn (II) Complexes Containing Salophen Ligand

The salophen ligand and its complexes of Ni(II), Co(II), Cu(II), and Mn(II) are explored in terms of synthesis, conductivity; magnetic measurements, elemental analysis, FT-IR; electronic spectra, and antibacterial activities. The 3D molecular modeling structures of the ligand and its metal complexes are obtained by using Argus lab software. The experimental data shows that the ligand is tetradentate and bonded to the metal ion via N2O2 donor atoms. Antibacterial activity of the synthesized compounds are checked against the microbes Bacillus cereus and Escherichia coli. The metal complexes exhibit antibacterial activity higher than that of the free ligand. This works contributes to the science of Schiff base compounds, in addition to stimulating the synthesis of new ligands and its complexes for the future advancement of coordination chemistry.

DNA interaction, docking, molecular modelling and biological studies of o-Vanillin derived Schiff base metal complexes

In the present studies, [Cu(ABOVL)]1, [Co(ABOVL)]2, [Cr (ABOVL)]3, and [Zn (ABOVL)]4 complexes were prepared where ABOVL is the condensation product of 2-hydroxy-3-methoxybenzaldehyde (o-Vanillin) and (2-aminophenyl)methanol (2-aminobenzylalcohol). To characterize ABOVL and its metal complexes standard analytical and spectral techniques were employed. From the spectral data, ABOVL acts as a bi-dentate ligand with O, N as donor atoms and complex I exhibited square planar geometry and complexes 2, 3, and 4 exhibited octahedral geometries respectively. DNA binding studies were performed using fluorescence, viscosity and absorption studies. The binding constant from absorption studies was 6.23 ± 0.04 × 104 M−1, 5.76 ± 0.03 × 104 M−1, 4.95 ± 0.07 × 104 M−1 and 4.12 ± 0.06 × 104 M−1 for 1, 2, 3 and 4 complexes respectively, and Stern-Volmer quenching constant, KSV from fluorescence studies was 3.99 × 103 M−1, 3.21 × 103 M−1, 2.78 × 103 M−1 and 2.53 × 103 M−1 for 1, 2, 3 and 4 complexes respectively. The above data signifies intercalative mode of binding of complexes to CT-DNA. Viscosity studies further revealed the binding of complexes to CT-DNA through intercalation. Nuclease studies of the complexes were carried out using supercoiled pUC19 DNA with hydrogen peroxide as an oxidant and the results were discussed. GOLO 3.1 programme (software) was used for docking studies and the results showed that complexes can effective bind with active receptor protein of DNA topoisomerase I involving hydrogen bonding interactions and the results were discussed. Antimicrobial studies performed by disc diffusion method showed that the complexes possess higher anti-microbial activity than compared to ABOVL. In-vitro cytotoxic studies were performed for the synthesized complexes against selected cell lines by MTT assay where Complex I showed potential inhibitory efficiency with an IC50 of 49.13 μg/mL as compared to other complexes. Molecular modelling studies were carried out using Argus lab.

Synthesis and Molecular Docking Study of Novel Hybrids of 1,3,4‐Oxadiazoles and Quinoxaline as a Potential Analgesic and Anti‐Inflammatory Agents

Novel hybrid molecules were synthesized through the amalgamation of quinoxaline residue with 1,3,4‐oxadiazole molecule. The purity of obtained 1,3,4‐oxadiazoles derivatives containing quinoxaline residue (total 11) was confirmed through thin‐layer chromatography, combustion analysis, and melting point, whereas their structures were confirmed by infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy. In animal studies, the derivatives 4‐(5‐(4‐(3‐methylquinoxalin‐2‐yl)phenyl)‐1,3,4‐oxadiazol‐2‐yl)benzenamine and 2‐(5‐(4‐(3‐methylquinoxalin‐2‐yl)phenyl)‐1,3,4‐oxadiazol‐2‐yl)benzenamine showed excellent analgesic and anti‐inflammatory activities, respectively, as compared with other derivatives. In order to rationalize the biological results of the derivatives, molecular docking studies were performed using Argus lab. The compounds exhibited good docking scores between −12.987 and −9.92 kcal/mol against cyclooxygenase‐II (5IKQ) protein fragment.

Synthesis, characterization and anti-fungal potential evaluation of 1, 4 thiazine derivatives by Mannich bases

Plan: The present research work is aimed to synthesize newer, less toxic and more effective Mannich bases of 1, 4 thiazine derivatives and further compare their antifungal activities. Preface: Microbial infections are becoming the most important issue for global health and economy. Among these fungal infections are the major problem these days. The morbidity and mortality of invasive fungal infections are unacceptably high. It is an urgent need for the development of new antifungal agents to treat these life-threatening invasive infections. Methodology: Mannich base was synthesized by using o-amino thiophenol with maleic anhydride. Further, four derivatives of Mannich bases were synthesized from 3-oxo-3, 4-dihydro-2H-1, 4-benzothiazin-2-yl) acetic acid with sulpha drugs, ethanol, and formaldehyde. Then synthesized Mannich bases were docked against Dihydrofolate reductase complexed with NADPH and 6- methyl-5- [3-methyl-3-(3,4,5-trimethoxyphenyl) but-1-yn-1-yl]pyrimidine-2,4-diamine (UCP115A)using Argus Lab software. On this basis, we selected 3QLS as a biological target for docking study of synthesized compound. Outcome: The structures of the synthesized compounds were confirmed by UV, IR and Mass Spectroscopic studies. All the newly synthesized derivatives were screened for antifungal activity against Candida albicans NCIM 3100 and Aspergillus niger NCIM 596 by agar diffusion method (Kirby- Bauer method) using fluconazole (10µg/disc) as the standard and dimethyl sulphoxide as the vehicle. The docking results indicate the Mannich bases of 1, 4-thiazines (ligand binding energy varies from -8.9046kcal/mol to -12,0457kcal/mol) shows considerable antifungal activity against Candida albicans. Out of the four derivatives, E4 (Sulfamethoxazole substituted 1, 4- thiazine) possess the best ligand pose energy (-12.0414 kcal/mol) and two hydrogen bond. Among these synthesized compounds, compound E4([4({[4-(N-(5-methyl-3-isoxazolyl) amino sulfonyl) phenyl] amino} methyl)-3-oxo-3,4-dihydro-2H1,4-benzothiazin-2yl] acetic acid) showed highest antifungal activity due to the presence of 1,4- thiazine with sulfamethoxazole substitution.

Synthesis, Characterization, Molecular Modeling, and Biological Evaluation of 1,2,4‐Triazole‐pyridine Hybrids as Potential Antimicrobial Agents

A novel 1,2,4‐triazole‐pyridine hybrid derivatives were synthesized by the reaction of nicotinohydrazide with carbon disulfide to yield potassium‐3‐pyridyl‐dithiocarbazate (I). This was further cyclized with ammonia solution to yield 5‐mercapto‐substituted 1,2,4‐triazole‐pyridine hybrid (II). This was finally reacted with different substituted benzyl derivatives to produce 1,2,4‐triazole‐pyridine hybrid derivatives (III). The purity of the derivatives was confirmed by thin‐layer chromatography and melting point. Structure of these derivatives was set up by determining its infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectroscopy. Further, the synthesized derivatives were evaluated for their in vitro antimicrobial activity against the three Gram‐negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Acinetbacter baumannii), three Gram‐positive bacteria (Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis), and two fungus (Aspergillus clavatus and Candida albicans). Minimal inhibitory concentration was also determined against same microorganism. Out of all synthesized derivatives, two derivatives, that is, 3‐(5‐(2‐bromobenzylthio)‐4H‐1,2,4‐triazol‐3‐yl)pyridine and 3‐(5‐(2,4‐dibromobenzylthio)‐4H‐1,2,4‐triazol‐3‐yl)pyridine showing more potent antibacterial activity.Docking studies were performed by using Argus lab, and all the derivatives exhibited good docking scores between −10.5369 and −11.8477 kcal/mol and were better as compared with standard drug methotrexate against a dihydrofolate reductase protein fragment from E. coli and Lactobacillus (4DFR). Among all compounds, 4h has shown the maximum docking score and found in agreement to in vitro antimicrobial studies.

Design, Synthesis, Characterisation and Biological Evaluation of some Novel 1, 3, 4 Thiadiazole Derivatives as Anti-tubercular agents Targeting Decaprenyl Phosphoryl Beta-D-Ribose 2 ’Epimerase-1

INTRODUCTION:Tuberculosis [TB] is caused by mycobacterium tuberculosis that most often affect the lungs. Tuberculosis is curable and preventable. In 1882, the German physician Robert Koch isolated the bacterium. Tuberculosis is contagious and airborne disease. In 1944, streptomycin was to treat tuberculosis [TB]. This amino glycoside interferes with protein biosynthesis through an interaction with the small 30s subunit of the ribosome. The discovery of Para amino salicylic acid in 1946 was quickly followed by the important discovery of Isoniazid [INH], as one of the most active anti-TB drugs used today. Inhibition of mycolic acids biosynthesis, one of the essential components of the mycobacterium cell wall was determined as the mechanism of action. Pyrazinamide [PZA] appeared as a potential Anti-TB drug in 1952. The TB treatment in the 1980s was a great success as it allowed to shorten the duration of the therapy from 9 to 6 months. Ethambutol [EMB] and Rifampin [RIF], the two last derivatives used in the TB first-line treatment, were discovered during the 60s. Ethambutol is an ethylenediamine discovered in 1961, which affects the cell wall by specifically targeting the polymerization of arabinogalactan and lipoarabinomannan. Finally, Rifampin appeared as a drug of choice for TB treatment around 1970, by acting on replicating and non-replicating mycobacteria. This derivative belongs to the rifampicin family and inhibits bacterial RNA synthesis by binding to the b-subunit of the DNA-dependent polymerase. AIM: The aim of this project is to design molecules with potential anti-tubercular activity that is capable of inhibiting cell wall synthesis by inhibiting Decaprenylphosphoryl-beta-D-ribose2-epimerase-1. The designed compounds will be synthesized, characterized and evaluated for biological activity and toxicity. OBJECTIVE:The compounds are designed and docked against a specific crucial target, Decaprenylphosphoryl-beta-D-ribose2epimerase-1.This is involved in the cell wall biosynthesis and Lipid metabolism. The synthesized compounds are expected to act on the same.SUMMARY:Decaprenylphosphoryl-beta-D-ribose 2-epimerase a critical enzyme for the growth of Mycobacterium tuberculosis was chosen for our study after review of literature. It belongs to the Oxidoreductase family. A database of 200 molecules with high prospects of inhibiting the target Dpre1 were carefully chosen by making changes to the known hit molecules, here the thiadiazole nucleus was chosen. Selected molecules were designed and docked against Dpre1 using Argus lab® software. Six molecules with good docking score [lower binding energy] and interactions were shortlisted for synthesis. Reaction conditions were optimized. The selected molecules were subjected to toxicity prediction assessment by OSIRIS® property explorer developed by Acetilon Pharmaceuticals limited which is available online. The results are color coded as green color which predicts the drug likeness and possibly better activity. The molecules were labelled as SDK1, SDK2, SDK3, SDK5, PAA, HA, and were synthesized with satisfactory yield. The purity of the synthesized compounds was ensured by repeated recrystallization. Further the compounds were evaluated by TLC and Melting point determination. The characterization of the synthesized compounds was done using Infra-red, Nuclear Magnetic Resonance [H1 NMR] and Mass spectrometric methods [LC-MS, GC-MS]. All the Synthesized compounds exhibited molecular ion peak (M+) of varying intensities. The final pure compounds were screened for Anti-mycobacterial activity by in vitro method called Micro plate Alamar Blue Assay [MABA]. The synthesized compounds showed sensitivity [Minimum inhibitory concentration] at 3.12mcg/ml. The standard drugs Pyrazinamide, Streptomycin, Ciprofloxacin exhibited anti mycobacterial activity at 3.125mcg/ml, 6.25mcg/ml, and 3.125mcg/ml concentrations respectively. This indicates that the synthesized compounds are as Potent as the standard drugs.CONCLUSION:All the compounds gave Docking score between -8.73 to 11.37 kcal/mol Pyrazinamide gave docking score 11.55kcal/mol for 4P8Y, Streptomycin gave docking score of 10.87kcal/mol for 4P8Y and Ciprofloxacin gave docking score of 11.25kcal/mol for 4P8Y. There is a correlation between the score and activities of all the compounds which were tested and compared with the standard drugs. This goes to prove that Decaprenyl phosphoryl beta-D-ribose 2’ epimerase-1’ (PDBID: 4P8Y) is a critical enzyme for anti-mycobacterial activity. So the fine tuning the structures of these compounds will yield molecules with better anti mycobacterial activity. Further structural modifications of the synthesized compounds will aid in the development of potential molecules against the tuberculosis pathogen.

Design, synthesis, characterization and biological evaluation of some novel 1, 3, 4 oxadiazole derivatives as anti-tubercular agents targeting L, D transpeptidase 2

INTRODUCTION:Tuberculosis is a contagious disease caused by bacteria called Mycobacterium tuberculosis and it is an air borne disease. Tuberculosis generally affects the lungs, but can also affect the other parts of the body. Tuberculosis is spread through the air when people who have active TB in their lungs cough, spit, speak, or sneeze. People with latent TB do not spread the disease. Active infection occurs more often in people with HIV/AIDS and in those who smoke. Tuberculosis is curable and preventable disease.AIM:The aim of this project is to develop potential antimycobacterial agents.OBJECTIVES: The objective of the project is to design and synthesize some compounds which will act on L, D Transpeptidase 2 and inhibit the cell wall synthesis of M. tuberculosis. SUMMARY: a) L, D-Transpeptidase-2 (3VYP) is a critical enzyme for the cell wall synthesis of Mycobacterium tuberculosis was chosen for study after review of literature. b) Selected molecules were designed and docked against L, D-Transpeptidase-2 (3VYP) using Argus lab® 4.0software. c) Molecules with good Docking score (lower binding energy) and interactions were shortlisted for synthesis. The reaction conditions were optimized. d) The selected molecules were subjected to Toxicity prediction assessments by OSIRIS® software. The results are color coded as green color which predicts the drug likeness. e) Compounds were synthesized by conventional method and labeled as SA, NA, VS1, VS2, VS4 and VS5. f) The purity of the synthesized compounds was ensured by repeated recrystallization. Further the compounds were evaluated by TLC and Melting point determination. g) The characterization of the synthesized compounds was done using Infra-red, Nuclear Magnetic Resonance (H1 NMR &C13NMR) and Mass spectroscopic methods (LC-MS, GC-MS) h) The pure compounds were screened for In-vitro Anti- tubercular activity by Micro plate Alamar Blue Assay (MABA). All compounds showed a significant anti-mycobacterium activity. i) Docking with other critical enzyme was carried out. CONCLUSION:1. Our work concludes that our synthesized molecules are effective in inhibiting the target enzyme L, D-Transpeptidase 2, which is important for the growth of Mycobacterium tuberculosis Cell wall. 2. All the 6 compounds gave Docking score between -8.30 to -9.74kcal/mol. There is correlation between the score and activities of all the 6 compounds which were tested and compared with the standard drugs. 3. Multi target docking was done for different critical enzymes of mycobacterium tuberculosis using Argus lab ®. From the results, the targeted enzyme l,dtranspeptidase 2 score was closer to the other two target ie., diaminopimelate epimerase and glutamine synthase. There was not much significant difference between the other two targeted compounds. 4. The minimum inhibitory concentration of the 6 synthesized compounds against H37RV ranged from 12.5 μg/ml which is better compared to that of the certain known Anti-TB agents. Pyrazinamide- 3.125μg/ml, Ciprofloxacin- 3.125μg/ml and Streptomycin- 6.25μg/ml. Further structural refinement to the structure of the synthesized compounds is expected to yield promising molecules against the pathogen Mycobacterium tuberculosis.