COMPUTATIONAL APPROACHES RELATED TO DRUG DISPOSITION

Drug disposition connects with the movement of drug molecules inside the body after administration irrespective with the route of administration. After entering the system, drug molecule and internal body systems comes under various pharmacokinetic interactions followed by observation of suitable biological activity. In this exhaustive process, physicochemical nature of the chemical substance and physiological nature of system makes this movement competitive. In this view, pharmacokinetic and toxic properties of the molecule regulates the destination of the molecule. Various computational processes are available for in silico pharmacokinetic assessment of drug molecule after absorption through biological membrane, distributed throughout the system based on the percent ionization or partition coefficient factors followed by biologically transformed into an another entity in presence of microsomal enzymes and finally excrete out from system using various cellular transport systems as well as related cellular toxicity behavior. In this chapter, we ensemble all the possible information related with the drug movement and related computational tools to understand the possible chemical and pathophysiological changes. Here detailed knowledge on database expedition, establishment of pharmacophore model, homology modelling based on sequence similarity, molecular docking study (rigid and flexible docking) and QSAR/QSPR study (with detailed process and available softwares) are provided. These diversely united informations actually helps a researcher to understand the factual movement of a drug molecule inside the system

ANTIHYPERGLYCEMIC ACTIVITY OF PHENYL AND ORTHO-HYDROXY PHENYL LINKED IMIDAZOLYL TRIAZOLO HYDROXAMIC ACID DERIVATIVES

Objective: The paradigm was to establish phenyl and ortho-hydroxy phenyl linked imidazolyl triazolo hydroxamic acid derivatives as an antihyperglycemic agent.Methods: 100 mg/Kg body weight dose of phenyl and ortho-hydroxy Phenyl linked Imidazolyl triazolo Hydroxamic Acid derivatives (FP1-FP12) and standard glibenclamide were administered per os (p.o.) in the streptozotocin-induced hyperglycemic rats by glucose oxidase-peroxidase method and statistically evaluated by one way analysis of variance.Results: FP3 was potent as compare to standard glibenclamide (P < 0.05-0.001) and FP6, FP9, and FP4 were also effective as an antihyperglycemic agent. The activity profile of the molecule was as follows FP9< FP10< FP4< FP6<FP12< FP3. This study reflects that presence of para methoxy phenyl group linked with phenyl group in surface recognition portion and imidazolyl triazole group in linker portion associated with a sulfamethyl hydroxamic acid group in metal identifying the part in case of FP3 was resemble for antihyperglycemic activity.Conclusion: It was concluded that compounds possessing electron releasing groups on the aromatic rings in the surface recognition part considerably enhanced the antihyperglycemic activity

Design, synthesis and antiproliferative activity of hydroxyacetamide derivatives against HeLa cervical carcinoma cell and breast cancer cell line

Purpose: To design and develop a new series of histone deacetylase inhibitors (FP1 - FP12) and evaluate their inhibitory activity against hydroxyacetamide (HDAC) enzyme mixture-derived HeLa cervical carcinoma cell and MCF-7.Methods: The designed molecules (FP1 - FP12) were docked using AUTODOCK 1.4.6. FP3 and FP8 showed higher interaction comparable to the prototypical HDACI. The designed series of 2-[[(3- Phenyl/substituted Phenyl-[4-{(4- (substituted phenyl)ethylidine-2-Phenyl-1,3-Imidazol-5-One}](-4H- 1,2,4-triazol-5-yl)sulfanyl]-N-hydroxyacetamide derivatives (FP1-FP12) was synthesized by merging 2- [(4-amino-3-phenyl-4H- 1, 2, 4-triazol-5-yl) sulfanyl]- N-hydroxyacetamide and 2-{[4-amino-3-(2- hydroxyphenyl)-4H-1,2, 4-triazol-5-yl]sulfanyl}-N hydroxyacetamide derivatives with aromatic substitutedoxazolone. The biological activity of the synthesized molecule (FP1-FP12) was evaluated against HDAC enzyme mixture-derived HeLa cervical carcinoma cell and breast cancer cell line (MCF-7).Results: HDAC inhibitory activity of FP10 showed higher IC50 (half-maximal  concentration inhibitory activity) of 0.09 μM, whereas standard SAHA molecule showed IC50 of 0.057 μM. On the other hand, FP9 exhibited higher GI50 (50 % of maximal concentration that inhibited cell proliferation) of 22.8 μM against MCF-7 cell line, compared with the standard, adriamycin, with GI50 of (-) 50.2 μM.Conclusion: Synthesis, spectral characterization, and evaluation of HDAC inhibition activity and in vitro anticancer evaluation of novel hydroxyacetamide derivatives against MCF-7 cell line have been achieved. The findings indicate the emergence of potentialanticancer compounds.Keywords: Molecular docking, Hydroxyacetamide derivative, Histone deacetylase inhibition activity, MCF-7 cell lin

Journal of PharmaSciTech In silico ADME-Toxicity Profiling, Prediction of Bioactivity and CNS Penetrating Properties of some Newer Resveratrol Analogues

Abstract In silico ADME Toxicity profiling showed an interesting results against the resveratrol and its designed ligands (D1-D16), that these ligands were permeable by intestinal (Human Colonic Carcioma Cell Line) CaCo2 cell line and D8, D9, D11, D13, D14, D15, D16 were inhibitor of CYP2C19 microsomal enzyme which were may be active against breast cancer cell line, as the D13, D16 were belong to the p-glycoprotein substrate so there was a chance of efflux in the case of absorption. As well as the toxicity profile checked against the estrogen and androgen receptor, mutagenicity, carcinogenicity, human ether a gogo cell line, LD value clarifies the basic picture of potency. As the detail mechanism of 50 resveratrol was not revealed, so the bioactivity profiling navigate the mechanism behind activity and finally the polar surface area, Log PS and Log BB value justify that molecule D1 was the better molecule which can cross the blood brain barrier. As well as there is a good correlation occurred 2 in between Log P and Log PS with the r value 0.7104 which can correlate with the brain penetration capacity of a molecule

Anti-inflammatory and analgesic activities of imidazolyl triazolo hydroxamic acid derivatives

280-285Hydroxamic acids are directly related with cancer and its progression. Long term exposure with inflammatory responses, dysplasia develops which leads to cancer. Metastasis of cancer and expression of transient potential receptor ankyrin-1 are known to cause severe pain. Here, we explored the possibility of developing newer hydroxamic acid derivatives as anti-inflammatory and analgesic agent. Animals were administered with 100 mg/kg dose of the synthesized imidazolyl triazolo hydroxamic acid derivatives (FP1-FP12) and 50 mg/kg dose of standard diclofenac sodium. Carrageenan induced rat paw edema and Eddy’s hot plate methods were considered for anti-inflammatory and analgesic activities. Among all the synthesized molecules, FP10 and FP4 were the most effective anti-inflammatory and analgesic agent, respectively. The activity profile of remaining molecules as anti-inflammatory agents was as follows: FP4>FP9> FP8> FP2 and as analgesic activity profile was FP10>FP3>FP8 >FP11 >FP2 > FP12. Presence of ethyl- benzyl and furan groups in linker portion of the structure minimized both the anti-inflammatory and analgesic activities. Results have shown that compounds with electron releasing groups considerably enhance both anti-inflammatory and analgesic activities

Hydroxamic acid - A novel molecule for anticancer therapy

Hydroxamic acid is a potent moiety not only in the field of cancer therapy but also as a mutagenic agent. Among the various derivatives of hydroxamic acid, SAHA (Suberoylanilide Hydroxamic Acid) is considered as a potent anticancer agent. Scientists from the different corner synthesized different hydroxamic acid moieties with some straight chain oxazole, thiadiazole, biphenyl moieties in the terminal position. Acetylation and deacetylation of histones of the core proteins of nucleosomes in chromatin play an important role in the regulation of gene expression. The level of acetylation of histones is established and maintained by two classes of enzymes, histone acetyltransferase and histone deacetylases, which have been identified as transcriptional coactivators and transcriptional corepressors, respectively. There is increasing evidence that aberrant histone acetylation has been linked to various malignant diseases. Great efforts are currently underway for the design of more potent and less toxic candidates for the treatment of cancer. In recent years, hydroxamic acid derivatives have attracted increasing attention for their potential as highly efficacious in combating various etiological factors associated with cancer. Our main intention to draw an attention is that this single functional moiety has not only fit in the receptor but also create a diversified activity

Hydroxyacetamide derivatives: Cytotoxicity, genotoxicity, antioxidative and metal chelating studies

831-837Cancer is one of the most life threatening noncommunicable diseases of mankind. In India, it has been estimated to have have caused 8.8 lakh deaths in 2016 alone, and 1.74 million more people are expected to be affected by 2020. Considerable research has gone into curing cancer including drugs based hydroxyacetamide derivatives. In the present study, we studied the cytotoxic, genotoxic, antioxidative and metal chelating activity of the synthesized hydroxyacetamide derivatives. We did brine shrimp lethality assay to examine cell toxicity effect, Allium cepa root tip genotoxicity assay to identify in vitro mutagenicity on mitotic cells, DPPH scavenging activity to measure its antioxidative property and metal chelating activity was used to synchronize the receptor enactment of the hydroxyacetamide subordinates.and histone deacetylase was a metalloenzyme, so Brine shrimp lethality assay of hydroxyacetamide derivatives (FP1-FP12) demonstrated that that best activity was exhibited by FP2 with 7.7 µg/mL in comparison to standard K2Cr2O7 with 13.83 µg/mL. As per Meyer theory, all the synthesized molecules were cytotoxic in nature. Genotoxicity study by Alium cepa assay demonstrated that chromosomal aberrations were seen in all phases of mitosis and FP1, FP4, FP5, FP11, FP12 data showed statistically significant as compared to the standard cyclophosphamide. Amongst them, FP10 showed the best % mitotic index with various chromosomal disorders such as C-mitosis, chromosomal bridge and sticky chromosome. Antioxidant studies were performed by DPPH free radical scavenging, reducing power assay and metal chelating ability. All the synthesized molecules indicated better reducing property and FP4 was the best molecule with free radical scavenging property in comparison to the standard ascorbic acid. FP4 showed better metal chelating activity as compared to standard EDTA. As per the outcomes, the synthesized molecules can be utilized as a better anticancer molecule to treat cancer

Anti-inflammatory and analgesic activities of imidazolyl triazolo hydroxamic acid derivatives

Hydroxamic acids are directly related with cancer and its progression. Long term exposure with inflammatory responses, dysplasia develops which leads to cancer. Metastasis of cancer and expression of transient potential receptor ankyrin-1 are known to cause severe pain. Here, we explored the possibility of developing newer hydroxamic acid derivatives as anti-inflammatory and analgesic agent. Animals were administered with 100 mg/kg dose of the synthesized imidazolyl triazolo hydroxamic acid derivatives (FP1-FP12) and 50 mg/kg dose of standard diclofenac sodium. Carrageenan induced rat paw edema and Eddy’s hot plate methods were considered for anti-inflammatory and analgesic activities. Among all the synthesized molecules, FP10 and FP4 were the most effective anti-inflammatory and analgesic agent, respectively. The activity profile of remaining molecules as anti-inflammatory agents was as follows: FP4>FP9> FP8> FP2 and as analgesic activity profile was FP10>FP3>FP8 >FP11 >FP2 > FP12. Presence of ethyl- benzyl and furan groups in linker portion of the structure minimized both the anti-inflammatory and analgesic activities. Results have shown that compounds with electron releasing groups considerably enhance both anti-inflammatory and analgesic activities

Geographical Distribution, Chemical Constituents and Activity Profile of Magnolia

Many Asian countries use the bark of the Magnolia for medicinal purposes. Magnolia has many medical uses, including regulating GI motility, treating cough and asthma, preventing cardiovascular disease, and treating mental illness and brain disorders. To date, 118 magnolia species have been discovered. However, the International Union for Conservation of Nature has designated 231 species as vulnerable and critically endangered. Magnolia leaves yielded 20 isolated chemicals, including 16 lignans with 6 distinct structural types, such as honokiol, veraguensin, sitosterol, and magliflonenone. Magnolia species show pharmacological activities like Neuroprotective, anti-cancer, Anti-microbial, Antiplatelets, Anti-asthmatic, Gastrointestinal, and Hormone regulation. Magnolia bark extracts such as honokiol 2',6-di-(5-propenyl)-1,1'-biphenyl-2,2'-diol, have been demonstrated to benefit health. In recent in vitro and preclinical research, honokiol was found to have anti-inflammatory, anti-angiogenic, anti-oxidative, and anti-cancer activities. Honokiol and magnolol prevented the thromboxane B2 synthesis in response to thrombin, arachidonic acid, and collagen. So, soon, if we cultivate and save the endangered magnolia species through biotechnological means, it will be a boon for mankind