Synthesis,evaluation, molecular docking,and molecular dynamics studies of novel N-(4-[pyridin-2-yloxy]benzyl)arylamine derivatives as potential antitubercular agents

A new series of novel triclosan (2,4,4′-trichloro-2′-hydroxydiphenylether) analogues were designed, synthesized, and screened for their in vitro antimycobacterial and antibacterial activities. Most of the compounds showed significant activity against Mycobacterium tuberculosis H37Rv strain with minimum inhibitory concentration (MIC) values in 20–40 μM range in GAST/Fe medium when compared with triclosan (43 μM) in the first week of assay, and after additional incubation, seven compounds, that is, 2a , 2c , 2g , 2h , 2i , 2j , and 2m , exhibited MIC values at the concentration of 20–40 μM. The compounds also showed more significant activity against Bacillus subtilis and Staphylococcus aureus. The synthesized compounds showed druggable properties, and the predicted ADME (absorption, distribution, metabolism, and excretion) properties were within the acceptable limits. The in silico studies predicted better interactions of compounds with target protein residues and a higher dock score in comparison with triclosan. Molecular dynamics simulation study of the most active compound 2i was performed in order to further explore the stability of the protein–ligand complex and the protein–ligand interaction in detail.     

truPK -- human pharmacokinetic models for quantitative ADME prediction

The use of in silico prediction of absorption, distribution, metabolism and excretion (ADME) properties is gaining acceptance as a useful assessment tool for early identification of likely drug candidate failures. However, it has been difficult to locate reliable models for the prediction of human pharmacokinetics (PK) in silico Currently available methods for estimating ADME and toxicity properties, such as in vitro and animal models, are not very predictive of what is observed in the clinic. Existing in silico ADME prediction tools concentrate on physicochemical properties, such as solubility, log P, rule-of-five compliance, Caco-2 permeability, blood-brain barrier and so on, or only classify drug-like candidates as 'poor', 'medium' or 'good' for a PK parameter, without ascribing values. Although physiology-based pharmacokinetic -models can predict ADME properties, they rely on using various measured properties as input for better accuracy. Strand Genomics has developed a tool, truPK, that predicts the properties of a molecule (bioavailability, protein binding, volume of distribution, elimination half-life and absorption rate) that affect its dose and dose frequency in humans. truPK's five models built using sophisticated machine methods have predicted with > 75% accuracies in external validation sets.     

Recent advances in the applications of radioisotopes in drug metabolism, toxicology and pharmacokinetics

Radioisotopes have proven to be an indispensable tool in biomedical research and have played a pivotal role in the investigation of absorption, distribution, metabolism and excretion (ADME) properties of new chemical entities over the past several decades. The main advantage of using radioisotopes in studying the disposition of new drug candidates is the ease of detection and the achievement of high sensitivity, especially when compounds with high specific activity are used. The recent advances and applications of radioisotopes in designing and conducting ADME studies and its impact in the field of drug metabolism and pharmacokinetics are discussed in this review.     

Fungal biofilm inhibition by piperazine‐sulphonamide linked Schiff bases: Design,synthesis, and biological evaluation

We report the synthesis of some new piperazine‐sulphonamide linked Schiff bases as fungal biofilm inhibitors with antibacterial and antifungal potential. The biofilm inhibition result of Candida albicans proposed that the compounds 6b (IC₅₀ = 32.1 μM) and 6j (IC₅₀ = 31.4 μM) showed higher inhibitory activity than the standard fluconazole (IC₅₀ = 40 μM). Compound 6d (MIC = 26.1 μg/mL) with a chloro group at the para position was found to be the most active antibacterial agent of the series against Bacillus subtilis when compared with the standard ciprofloxacin (MIC = 50 μg/mL). Compound 6j (MIC = 39.6 μg/mL) with an OH? group at the ortho position showed more potent antifungal activity as compared to that of the standard fluconazole (IC₅₀ = 50 μM) against C. albicans. Thus, the synthesized compounds 6a–k were found to be potent biofilm inhibitors as well as active antibacterial and antifungal agents. The molecular docking study of the synthesized compounds against the secreted aspartyl protease (SAP5) enzyme of C. albicans exhibited good binding properties. The in silico ADME properties of the synthesized compounds were also analyzed and showed their potential to be developed as potential oral drug candidates.

     

Decreasing HepG2 Cytotoxicity by Lowering the Lipophilicity of Benzo[d]oxazolephosphinate Ester Utrophin Modulators

Utrophin modulation is a disease-modifying therapeutic strategy for Duchenne muscular dystrophy that would be applicable to all patient populations. To improve the suboptimal profile of ezutromid, the first-in-class clinical candidate, a second generation of utrophin modulators bearing a phosphinate ester moiety was developed. This modification significantly improved the physicochemical and ADME properties, but one of the main lead molecules was found to have dose-limiting hepatotoxicity. In this work we describe how less lipophilic analogues retained utrophin modulatory activity in a reporter gene assay, upregulated utrophin protein in dystrophic mouse muscle cells, but also had improved physicochemical and ADME properties. Notably, ClogP was found to directly correlate with pIC₅₀ in HepG2 cells, hence leading to a potentially safer toxicological profiles in this series. Compound 21 showed a balanced profile (H2K EC₅₀: 4.17 μM, solubility: 477 μM, mouse hepatocyte T_1/2 > 240 min) and increased utrophin protein 1.6-fold in a Western blot assay.     

Molecular docking, QPLD, and ADME prediction studies on HIV-1 integrase leads

HIV-1 integrase (IN) is an important drug target over the years with diverse therapeutic potential with the objective of designing new chemical entities with enhanced inhibitory potencies against HIV-1 IN. We performed molecular docking, quantum polarized ligand docking (QPLD), ADME screening, and PASS biological activity prediction studies on Raltegravir, Elvitegravir, and newly searched compounds of Cambridge crystallographic database. Best docking and QPLD scores of known and unknown searched compounds were compared using docking score, docking energy, and emodel energy. Moreover, correlation between docking score, docking energy with emodel energy yielded a statistically significant correlation coefficient. The searched compounds were also evaluated with ADME properties and biological activity prediction analysis. These compounds also show good pharmacokinetic properties under the acceptable range including antiviral biological activity prediction. Hence, these compounds could be employed to design ligands with enhanced inhibitory potencies and to predict the potencies of analogs to guide synthesis/or prepare synthetic analogs for second generation drug development against HIV-1 IN.     

Synthesis,crystal structure,and ADME prediction studies of novel imidazopyrimidines as antibacterial and cytotoxic agents

In the present study, a novel series of polyfunctionalized imidazopyrimidines 6a–u and 9a–d were efficiently constructed by a domino reaction between 2-imino-6-substituted-2,3-dihydropyrimidin-4(1H)-ones 4a–d or 8a–c and 2-bromoacetophenones 5a–i under mild basic conditions. The synthesized series were screened for their antibacterial activity against Staphylococcus aureus and Bacillus subtilis as Gram-positive (+) bacteria, as well as against Gram-negative (−) bacteria Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella typhi. Most of the synthesized derivatives of imidazopyrimidines 6 and 9 showed remarkable selectivity against Gram(−) bacteria over the Gram(+) ones. Compounds 6c , 6f , and 6g displayed potent and broad-spectrum antibacterial activity against all tested strains. Compounds 6f and 6g displayed promising inhibitory activity on GryB ATPase from E. coli with IC₅₀ = 1.14 and 0.73 μM, respectively. Simultaneously, some of the synthesized imidazopyrimidines were screened for their antiproliferative activity against 60 cancer cell lines at a concentration of 10 μM. Compound 9d showed potent activity against most of the tested cell lines, with a mean growth inhibition of 37%. The ADME (absorption, distribution, metabolism, and excretion) prediction study demonstrated that the synthesized hits have, in addition to their promising chemotherapeutic activity, acceptable pharmacokinetic properties, and a drug-likeness nature to be further developed.     

基于网络药理学的黄精抗肿瘤成分筛选研究

目的 探讨黄精抗肿瘤的药效物质基础及分子作用机制。方法 采用中药网络药理学数据库和分析平台（TCMSP）对黄精的化学成分进行收集，借助计算机辅助预测吸收、分布、代谢和排泄（ADME）性质并结合obioavail 1.1和pre-Caco-2预测模型对活性成分群进行初筛；对所有潜在活性成分进行靶点识别；采用Cytoscape3.6.1软件进行“活性成分-靶标”网络的构建，并利用“network analyzer”插件对网络的拓扑性质进行分析；采用在线分析工具DAVID进行KEGG通路富集分析。结果 黄精中已鉴定的39个化合物，其中18个具有良好的ADME性质的化合物，这些潜在的活性成分中，共有14个活性成分及其对应的19靶标与黄精抗肿瘤的活性密切相关。通过构建“活性成分-靶点”网络及对网络进行分析，共获得个4关键化合物：黄芩素、3’-甲氧基大豆苷元、异甘草素、（2R）-7-羟基-2-（4-羟苯基）-4-苯丙二氢呋喃；2个关键靶标：前列腺素G/H合酶2、热休克蛋白90AA1。在对靶点进行KEGG通路分析时，共获得12条与抗肿瘤相关的通路。结论 黄精可通过多成分、多靶点及多通路的作用机制发挥其抗肿瘤活性。     

Drug-like properties and the causes of poor solubility and poor permeability

There are currently about 10000 drug-like compounds. These are sparsely, rather than uniformly, distributed through chemistry space. True diversity does not exist in experimental combinatorial chemistry screening libraries. Absorption, distribution, metabolism, and excretion (ADME) and chemical reactivity-related toxicity is low, while biological receptor activity is higher dimensional in chemistry space, and this is partly explainable by evolutionary pressures on ADME to deal with endobiotics and exobiotics. ADME is hard to predict for large data sets because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Currently, screening for biological receptor activity precedes or is concurrent with screening for properties related to "drugability." In the future, "drugability" screening may precede biological receptor activity screening. The level of permeability or solubility needed for oral absorption is related to potency. The relative importance of poor solubility and poor permeability towards the problem of poor oral absorption depends on the research approach used for lead generation. A "rational drug design" approach as exemplified by Merck advanced clinical candidates leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and, hence, poorer permeability. A high throughput screening (HTS)-based approach as exemplified by unpublished data on Pfizer (Groton, CT) early candidates leads to higher molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility.     

QSAR studies of antibacterial ricinoleic acid derivatives

A series of ricinoleic acid derivatives has been synthesized and tested for antibacterial activity with respect to four standard strains. Dibromoricinoleic acid (DBRA) showed high activity comparable with that of the reference drug ciprofloxacin. QSARs between various physicochemical indices and the antibacterial activity of a training set including 12 compounds were analyzed. The topological parameter, the valence second-order molecular connectivity index (²χ^v), and the electronic parameter of total energy (TE) proved to be important for the antibacterial activity of compounds studied. The proposed QSAR models were validated using the leave-one-out procedure. The validity of these models was confirmed by predicting the activity of a set of three compounds (not present in the training set). __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 3, pp. 16–21, March, 2007.     

ADME properties of herbal medicines in humans: evidence, challenges and strategies

Herbal medicines, an important group of multicomponent therapeutics, are widely and increasignly used worldwide. Despite the popularitiy of herbal medicines, the clinical evidence that support the use of most herbal medicines is weak. Pharmacokinetic and absorption, distribution, metabolism and excretion (ADME) studies have been integrated into modern drug development, but ADME studies are generally not needed for herbal remedy discovery and development. For the majority of herbal medicines, data on their ADME and pharmacokinetic properties in humans are lacking or scant. An extensive literature search indicates that there are limited data on ADME properties of herbal medicines in humans. Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp/MDR1/ABCB1) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are critical determining factors for the in vivo ADME processes of herbal remedies. There are increasing ADME studies of herbal remedies, but these studies are mainly focused on a small number of herbal medicines including St John's wort, milk thistle, curcumin, echinacea, ginseng, ginkgo, and ginger. For an herbal medicine, the pharmacological activity is gained when the active agents or the active metabolites reach and sustain proper levels at their sites of action. Both the dose levels and ADME processes of active herbal components in the body govern their target-site concentrations and thus the therapeutic responses. In this regard, a safe and optimal use of herbal medicines requires a full understanding of their ADME profiles. To optimize the use of herbal remedies, further studies to explore their ADME properties in humans are certainly warranted.     

The emerging importance of predictive ADME simulation in drug discovery.

Absorption, distribution, metabolism and excretion (ADME) studies, are widely used in drug discovery to optimize the balance of properties necessary to convert leads into good medicines. However, throughput using traditional methods is now too low to support recent developments in combinatorial and library chemistry, which have generated many more molecules of interest. To the more enlightened practitioners of ADME science, this situation is generating both the problem and the solution: an opportunity is now forming, with the use of higher throughput ADME screens and computational models, to access this wide chemical diversity and to dissect out the rules that dictate a pharmacokinetic or metabolic profile. In the future we could see ADME properties designed-in from the first principles in drug design.     

Pharmaceutical and pharmacological evaluation of Burow's solution (aluminum acetate solution), hospital preparation, and development of its rapid preparation method

Burow's solution, or aluminum acetate solution, is effective in inhibiting various microorganisms including methicillin-resistant Staphylococcus aureus (MRSA) that are commonly observed in chronic suppurative otitis media. It takes several days to prepare Burow's solution using aluminum sulfate, and the pharmaceutical properties of the solution are not fully understood. In this study, the effect of storage (5 months) of Burow's solution prepared according to the Teine-Keijin Hospital manual on its pharmaceutical properties and antibacterial activities was examined. We also attempted to develop a rapid preparation method of aluminum acetate (or 1.7% aluminum) solution using two commercially available compounds of aluminum acetate basic (Al(2)O(CH(3)CO(2))(4), Al(OH)(CH(3)CO(2))(2)). The properties of Burow's solution, pH, osmolarity and antibacterial activity, were the same among different preparations and its storage for 5 months at 4 degrees C had no effect on these properties. The antibacterial potency of Burow's solution was dependent on aluminum concentration and its antibacterial potency against S. aureus and several MRSA strains was of the same magnitude. In a rapid preparation, aluminum acetate basic was mixed with appropriate amounts of tartaric acid and acetic acid, and the suspension was boiled for 2-2.5 hr until dissolved. The rapidly prepared aluminum acetate solution showed the same pharmaceutical properties and antibacterial activities as those of Burow's solution. The newly developed preparation method for aluminum acetate solution is expected to be convenient and feasible for hospital treatment of chronic suppurative otitis media.