Benzofuran Derivatives from Cortex Mori Radicis and Their Cholinesterase-Inhibitory Activity.

The phytochemical investigation of Cortex Mori Radicis led to the isolation and identification of a new prenylated benzofuranone (1) and four ring-opening derivatives (2-5) named albaphenol A-E, as well as nigranol A (6), together with ten 2-arylbenzofuran derivatives (7-16). The characterization of the structures of the new compounds and the structural revision of nigranol A (6) were conducted using the comprehensive analysis of spectroscopic data (1D/2D NMR, HRESIMS, CD, and XRD). Compounds 1-16 were tested for their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1 and 4 showed weak BChE-inhibitory activity (IC50 45.5 and 61.0 µM); six 2-arylbenzofuran derivatives showed more-potent BChE-inhibitory activity (IC50 2.5-32.8 µM) than the positive control galantamine (IC50 35.3 µM), while being inactive or weakly inhibitory toward AChE. Cathafuran C (14) exhibited the most potent and selective inhibitory activity against BChE in a competitive manner, with a Ki value of 1.7 µM. The structure-activity relationships of the benzofuran-type stilbenes were discussed. Furthermore, molecular docking and dynamic simulations were performed to clarify the interactions of the inhibitor-enzyme complex.

Targeting NAD Metabolism: Rational Design, Synthesis and In Vitro Evaluation of NAMPT/PARP1 Dual-Target Inhibitors as Anti-Breast Cancer Agents.

The malignancy of breast cancer poses a global challenge, with existing treatments often falling short of desired efficacy. Extensive research has underscored the effectiveness of targeting the metabolism of nicotinamide adenine dinucleotide (NAD), a pivotal molecule crucial for cancer cell survival and growth, as a promising anticancer strategy. Within mammalian cells, sustaining optimal NAD concentrations relies on two key enzymes, namely nicotinamide phosphoribosyltransferase (NAMPT) and poly(ADP-ribose) polymer 1 (PARP1). Recent studies have accentuated the potential benefits of combining NAMPT inhibitors and PARP1 inhibitors to enhance therapeutic outcomes, particularly in breast cancer. In this study, we designed and synthesized eleven novel NAMPT/PARP1 dual-target inhibitors. Among them, compound DDY02 exhibited acceptable inhibitory activities against both NAMPT and PARP1, with IC50 values of 0.01 and 0.05 µM, respectively. Moreover, in vitro evaluations revealed that treatment with DDY02 resulted in proliferation inhibition, NAD depletion, DNA damage, apoptosis, and migration inhibition in MDA-MB-468 cells. These results posit DDY02, by targeting NAD metabolism through inhibiting both NAMPT and PARP1, as a promising lead compound for the development of breast cancer therapy.

Discovery of potential Q-marker of traditional Chinese medicine based on chemical profiling, chemometrics, network pharmacology, and molecular docking: Centipeda minima as an example.

INTRODUCTION: The characteristics of chemical components or groups of chemical components in traditional Chinese medicines (TCMs) determine their clinical efficacy. Quality markers (Q-markers) is of great significance for standardizing the quality control system of TCM. OBJECTIVES: We aimed to develop a new strategy to discover potential Q-markers of TCM by integrating chemometrics, network pharmacology, and molecular docking, using Centipeda minima (also known as ebushicao [EBSC]) as an example. MATERIALS AND METHODS: First, fingerprints of different batches of EBSC and its counterfeit Arenaria oreophila (also known as zaozhui [ZZ]) were established. Second, chemometric analysis was conducted to determine the influence of varying authenticity/batches of herbs on quality and the chemical markers were screened out. Third, network pharmacology and molecular docking simulations were used to verify the relationship between active ingredients and targets. Lastly, potential Q-markers were selected based on TCM theory. RESULTS: The chemical profiles of EBSC and ZZ were investigated. It was found that different batches of EBSC have differences in chemical composition. Based on our chemometric analysis, chlorogenic acid, rutin, isochlorogenic acid A, quercetin, arnicolide D, and brevilin A were selected as candidate active ingredients. ATIL6, EGFR, CASP3, MYC, HIF1A, and VEGFA were the main targets. Molecular docking was used to verify the binding ability. Based on the concept of Q-marker, arnicolide D and brevilin A were identified as potential Q-markers for EBSC. CONCLUSIONS: Our strategy could be used as a practical approach to discover Q-markers of TCM to evaluate overall chemical consistency.

Analysis of five active ingredients of Er-Zhi-Wan, a traditional Chinese medicine water-honeyed pill, using the biopharmaceutics classification system.

Er-Zhi-Wan (EZW) is a traditional Chinese medicine with many clinical applications and used as a health product in East Asia. Five active ingredients (salidroside, specnuezhenide, nuezhenoside, luteolin, and oleanolic acid) were screened out from EZW to develop an in vitro rapid evaluation method for the classification of in vivo drug absorption behavior by biopharmaceutics classification system (BCS). Ultra-performance liquid chromatography was used for quantitative analysis. Solubility and permeability were assayed by equilibrium solubility and multiple models: everted rat intestinal sac model, cultured Caco-2 cells, octanol-water partition coefficient (LogP) method. The BCS properties of drugs were predicted using software applications, and the correlations of measured and predicted values of factors affecting oral drug absorption were calculated. The results were verified by measuring the absolute bioavailability of the active ingredients. Salidroside, specnuezhenide, and nuezhenoside were classified as BCS class III drugs, and luteolin was classified as a BCS class III/I drug because of the difference in LogP and intestinal permeability. Oleanolic acid was classified as a BCS class II/IV drug in acidic media and BCS class I/III drug in other media. Overall, EZW may be classified as a BCS class III drug, and permeability was identified as the primary factor limiting absorption. The results provide a novel method for the evaluation of the in vivo absorption of oral traditional Chinese medicines.

Evaluation of Anti-Inflammatory Activities of a Triterpene ß-Elemonic Acid in Frankincense In Vivo and In Vitro.

The purpose of this research was to extract and separate the compounds from frankincense, and then evaluate their anti-inflammatory effects. The isolated compound was a representative tetracyclic triterpenes of glycine structure according to ¹H-NMR and 13C-NMR spectra, which is ß-elemonic acid (ß-EA). We determined the content of six different localities of frankincense; the average content of ß-EA was 41.96 mg/g. The toxic effects of ß-EA administration (400, 200, 100 mg/kg) for four weeks in Kunming (KM) mice were observed. Compared with the control group, the body weight of mice, the visceral coefficients and serum indicators in the ß-EA groups showed no systematic variations. The anti-inflammatory effects of ß-EA were evaluated in LPS-induced RAW264.7 cells, xylene-induced induced ear inflammation in mice, carrageenin-induced paw edema in mice, and cotton pellet induced granuloma formation in rats. ß-EA inhibited overproduction of tumor necrosis factor-α(TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein 1 (MCP-1), soluble TNF receptor 1 (sTNF R1), Eotaxin-2, Interleukin 10 (IL-10) and granulocyte colony-stimulating factor (GCSF) in the RAW264.7 cells. Intragastric administration with ß-EA (300, 200, and 100 mg/kg in mice, and 210, 140, and 70 mg/kg in rats) all produced distinct anti-inflammatory effects in vivo in a dose-dependent manner. Following treatment with ß-EA (300 mg/kg, i.g.), the NO level in mice ears and PGE2 in mice paws both decreased (p < 0.01). In conclusion, our study indicates that ß-EA could be a potential anti-inflammatory agent for the treatment of inflammatory diseases.

Discrimination of Polygoni Multiflori radix and Cynanchi Auriculati radix using ultra-high performance liquid chromatography fingerprints and chemical pattern recognition.

In this work, a strategy was proposed to discriminate Polygoni Multiflori Radix (PMR) and its adulterant (Cynanchi Auriculati Radix, CAR). Ultra-high performance liquid chromatography (UHPLC) fingerprints were established to analyze samples containing PMR, CAR and mixtures simultaneously. Multivariate classification methods were applied to analyze the obtained UHPLC fingerprints, including principal component analysis (PCA), partial least square discriminant analysis (PLS-DA), soft independent modeling of class analogy (SIMCA), support vector machine discriminant analysis (SVMDA) and counter-propagation artificial neural network (CP-ANN). A plot of PCA score showed that PMR and CAR samples belonged to separate clusters (PMR class and CAR class), and samples of mixtures were located near PMR or CAR classes. Analysis by PLS-DA, SVMDA and CP-ANN performed well for recognition and prediction in terms of PMR and CAR samples. Moreover, the PLS-DA method performed best in the detection of adulterated samples, even if the adulterant was about 25%.

Injection of hTERT-Transduced Endothelial Progenitor Cells Promotes Beneficial Aortic Changes in a High-Fat Dietary Model of Early Atherosclerosis.

OBJECTIVES: Cultured endothelial progenitor cells (EPCs) display troubling issues that adversely affect their applicability to endothelial regeneration. We hypothesized that transduction of the human telomerase catalytic subunit (hTERT) gene would enhance EPC function in treating dietary-induced early atherosclerosis (AS). METHODS: A dietary-induced early AS model was successfully constructed in 90 healthy male rats, while 30 healthy control (HC) rats were normally fed. Four experimental groups were constructed: an untreated HC group; an untreated AS group injected with PBS; a null EPC AS group injected with null vector-transduced EPCs, and an hTERT EPC AS group injected with hTERT-transduced EPCs. Two months postinjection, abdominal aortas were extracted to validate EPC integration and comparatively assess mRNA and protein expression of the early atherosclerotic markers VCAM-1, ICAM-1, LFA-1, Mac-1, CD44, MCP-1, endothelial nitric oxide synthase (eNOS), and apolipoprotein E. RESULTS: In vitro, hTERT transduction of EPCs resulted in a significantly superior proliferative capacity as well as significantly higher NO, iNOS, and LDH secretory capacity. In vivo injection of hTERT-transduced EPCs produced significant reductions in CD44 and MCP-1 expression as well as a significant increase in eNOS expression relative to injection with null vector-transduced EPCs (all p < 0.05). CONCLUSION: hTERT-transduced human EPCs may be useful in treating dietary-induced early AS.

Phenolic compounds from Bletilla striata.

Two new malic acid derivatives, namely eucomic acid 1-methyl ester (2) and 6'''-acetylmilitaline (7), together with ten known compounds (1, 3-6, 8-12), were isolated from the dry tubers of Bletilla striata (Thunb.) Reichb. F., a perennial traditional Chinese medicinal herb, which was used for the treatment of pneumonophthisis, pneumonorrhagia, tuberculosis, and hemorrhage of the stomach or lung. Their structures were elucidated by spectroscopic analyses, including 1D-, 2D-NMR, and HR-ESI-MS.

[Comparison of Six Flavonoid Components of Closely-Related Plants Agrimonia pilosa,Potentilla chinensis and Potentilla discolor].

Objective: To establish an UHPLC method for simultaneous determination of six flavonoid components of three closelyrelated plants Agrimonia pilosa,Potentilla chinensis and Potentilla discolor including rutin,hyperoside,cynaroside,quercetin,apigenin and kaempferol. Meanwhile three fresh and dry plants were evaluated to compare the contents of six flavonoid components. Methods: The samples were pretreated with ultrasonic extraction with 70% ethanol for 0. 5 h. The analysis was performed on an Acquity HSS T3( 100 mm × 3. 0 mm,1. 8 µm) column with the mobile phase consisting of acetonitrile and 0. 3% glacial acetic acid aqueous at a flow rate of0. 4 m L / min. The detection wavelength was 360 nm,and the column temperature was 35 ℃. Results: The contents of rutin and hyperoside were high generally,but the content of kaempferol was extremely low in three closely-related plants. The content of apigenin was0. 028 mg / g in Potentilla chinensis,but not detected in Agrimonia pilosa and Potentilla discolor. The content of cymaroside in Agrimonia pilosa was significantly higher than that in Potentilla chinensis and Potentilla discolor. The fresh plants of Potentilla chinensis and Potentilla discolor contained more flavonoids than oven drying plants. Conclusion: The similar trend of content change from fresh to dry plant has showed a chemotaxonomic relationship of Potentilla chinensis and Potentilla discolor. The established determination method is simple,rapid and efficient,and is applicable for analysis of the contents of flavonoids in three closely-related plants,which provides the scientific basis for rationalization of using these drugs in clinic.

[Identification of liposoluble constituents in Yushu tablets by UPLC-ESI-IT-TOF/MS].

In order to identify the chemical constituents of Yushu tablets comprehensively, we studied the chemical constituents of CHCl3 extract from Yushu tablets by the ultra performance liquid chromatography-electrospray ionization-ion trap-time of flight mass spectrometry (UPLC-ESI-IT-TOF/MS). It showed that there were more than 100 compounds separated, and forty-nine peaks among these were identified on the basis of high resolution mass spectrometry data and literature data reported. Determination of twelve peaks was further confirmed by standard substances. These components assigned to the different plant sources mainly included phenylpropanoids, triterpenoids, quinones and m-trihydroxybenzene compounds. By analyzing the chemical components of CHCl3 extract from compound Chinese medicine Yushu tablets comprehensively, this study provided the foundation for studying chemical components, pharmacodynamic substance and quality control of Yushu tablets.

[Simultaneous Determination of Five Astragalosides in Astragali Radix and Jinqi Jiangtang Tablet by HPLC-ELSD].

OBJECTIVE: To develop an HPLC-ELSD method for simultaneous determination of Astragaloside IV Astragaloside I, Astragaloside II, Astragaloside III and Isostragaloside II in Astragali Radix and Jinqi Jiangtang tablet. METHODS: The chromatographic conditions were as follows: Grace Apollo C18 column (250 mm x 4. 6 mm, 5 µm), acetonitrile (A) and water(B) as mobile phases for gradient elution, and the flow rate being 1. 0 mL/min. RESULTS: Five components showed good linearity. The average recoveries were between 95% - 105%. Five Astragalosides were determined in twelve batches of Astragali Radix and ten batches of Jinqi Jiangtang tablet. CONCLUSION: This is a specific, sensitive and simple method for simultaneous determination of Astragaloside IV, Astragaloside I Astragaloside II, Astragaloside III and Isostragaloside II in Astragali Radix and Jinqi Jiangtang tablet.

Hyaluronan Mediates Cold-Induced Adipose Tissue Beiging.

Adipose tissue beiging refers to the process by which beige adipocytes emerge in classical white adipose tissue depots. Beige adipocytes dissipate chemical energy and secrete adipokines, such as classical brown adipocytes, to improve systemic metabolism, which is beneficial for people with obesity and metabolic diseases. Cold exposure and ß3-adrenergic receptor (AR) agonist treatment are two commonly used stimuli for increasing beige adipocytes in mice; however, their underlying biological processes are different. Transcriptional analysis of inguinal white adipose tissue (iWAT) has revealed that changes in extracellular matrix (ECM) pathway genes are specific to cold exposure. Hyaluronic acid (HA), a non-sulfated linear polysaccharide produced by nearly all cells, is one of the most common components of ECM. We found that cold exposure significantly increased iWAT HA levels, whereas the ß3-AR agonist CL316,243 did not. Increasing HA levels in iWAT by Has2 overexpression significantly increases cold-induced adipose tissue beiging; in contrast, decreasing HA by Spam1 overexpression, which encodes a hyaluronidase that digests HA, significantly decreases cold-induced iWAT beiging. All these data implicate a role of HA in promoting adipose tissue beiging, which is unique to cold exposure. Given the failure of ß3-AR agonists in clinical trials for obesity and metabolic diseases, increasing HA could serve as a new approach for recruiting more beige adipocytes to combat metabolic diseases.

Rapid identification of various chemical components in Cinnamomi ramulus by UPLC-Q-Orbitrap-MS.

Cinnamomi ramulus (CR) is a common Chinese herbal medicine with a long history. It is often used to treat exogenous wind-cold diseases in clinic, but its chemical compositions remain to be studied. In this study, CR was extracted with 75% ethanol, and UPLC-Q-Orbitrap-MS combined with data post-processing method was used to identify the chemical components in the extract. Through this technology, the components in CR can be separated and accurately identified. A total of 61 compounds were identified, including 14 simple phenylpropanoids, 3 coumarins, 5 lignans, 14 flavonoids, 10 benzoic acids, 8 organic acids, and 7 others. This study confirmed the existence of these compounds in CR and speculated the cleavage pathways of each compound, which enriched the mass spectrometry data and cleavage rules. This study can provide a reference for CR and other research.

STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib.

There have been major advances in defining the immunological events associated with fibrosis in various chronic liver diseases. We have taken advantage of this data to focus on the mechanisms of action of a unique multi-kinase inhibitor, coined sorafenib, on CCl4-induced murine liver fibrosis, including the effects of this agent in models of both acute and chronic CCl4-mediated pathology. Importantly, sorafenib significantly attenuated chronic liver injury and fibrosis, including reduction in liver inflammation and histopathology as well as decreased expression of liver fibrosis-related genes, including α-smooth muscle actin, collagen, matrix metalloproteinases and the tissue inhibitor of metalloproteinase-1. Furthermore, sorafenib treatment resulted in translocation of cytoplasmic STAT3 to the nucleus in its active form. Based on this observation, we used hepatocyte-specific STAT3 knockout (STAT3(Hep-/-)) mice to demonstrate that hepatic STAT3 was critical for sorafenib-mediated protection against liver fibrosis, and that the upregulation of STAT3 phosphorylation was dependent on Kupffer cell-derived IL-6. In conclusion, these data reflect the clinical potential of the multi-kinase inhibitor sorafenib for the prevention of fibrosis as well as the treatment of established liver fibrosis and illustrate the immunological mechanisms that underlie the protective effects of sorafenib.

Advances in the treatment of hepatogenous diabetes: A review.

Hepatogenous diabetes (HD) is a glycogen metabolism disorder that arises as a consequence of chronic liver disease. The condition is frequently detected in patients diagnosed with cirrhosis, which is a result of advanced liver disease. The prognosis for patients with HD is generally poor, and they are at a heightened risk for serious complications such as gastrointestinal bleeding, primary peritonitis, and hepatic encephalopathy. Hepatogenous diabetes progression is often associated with cirrhosis progression, which leads to the development of liver cancer and increased patient mortality. Despite the prevalence and severity of HD, no systematic treatment strategy for clinical management of the condition has been proposed by any research or institutions to date. This paper conducts an extensive review of recent advancements in HD treatment in the quest for an effective treatment approach that may improve the overall prognosis of HD.

Xanthones as potential α-glucosidase non-competition inhibitors: Synthesis, inhibitory activities, and in silico studies.

α-glucosidase inhibitors (AGIs) were commonly used in clinical for the treatment of type 2 diabetes. Xanthones were naturally occurring antioxidants, and they may also be potential AGIs. In this study, eleven 1,6- and 1,3-substituted xanthone compounds were designed and synthesized, of which four were new compounds. Their α-glucosidase inhibitory activities in vitro and in silico were evaluated. Five xanthone compounds with higher activity than acarbose were screened out, and the xanthones substituted at the 1,6-positions were more likely to be potential α-glucosidase non-competitive inhibitors. The binding mode of xanthones with α-glucosidase was further studied by molecular docking method, and the results showed that the inhibitory effect of non-competitive inhibitors on site 1 of α-glucosidase may be related to the hydrogen bonds formed by the compounds with amino acid residues ASN165, HIS209, TRY207, ASP243, and SER104. This study provided a theoretical basis of the rapid discovery and structural modification of non-competitive xanthone inhibitors of α-glucosidase.

Insight on Structural Modification, Cytotoxic or Anti-Proliferative Activity, Structure-Activity Relationship of Berberine Derivatives.

Berberine (BBR) is a quaternary ammonium alkaloid isolated from the Traditional Chinese Medicine Coptis chinensis. It possesses a plethora of pharmacological activities because its unique structure properties make it readily interact with macromolecules through π-π stacking and electrostatic interaction. Its anti-tumor effects are receiving more and more attention in recent years. Cytotoxicity and anti-proliferation are the important anti-tumor modes of BBR, which have been studied by many research groups. This study aims to review the structural modifications of BBR and its cytotoxic derivatives. Also, to study the corresponding structure-activity relationship. BBR showed potential activities toward tumor cells, however, its modest activity and poor physicochemical properties hindered its application in clinical. Structural modification is a common and effective approach to improve BBR's cytotoxic or anti-proliferative activities. The structural modifications of BBR, the cytotoxic or anti-proliferative activities of its derivatives, and the corresponding structure-activity relationship (SAR) were summarized in the review. The concluded SAR of BBR derivatives with their cytotoxic or anti-proliferative activities will provide great prospects for the future anti-tumor drug design with BBR as the lead compound.

Identification of the Origin, Authenticity and Quality of Panax Japonicus Based on a Multistrategy Platform.

BACKGROUND: Panax Japonicus (PJ) is a widely used Chinese herbal medicine, functional food and tonic. However, its origin has a great influence on the quality of PJ, and with the increasing demand for PJ, fake and inferior products, such as Panax Stipuleanatus (PS), often appear. The identification of the origin and authenticity of PJ is critical for ensuring the quality, safety and effectiveness of drugs. OBJECTIVE: Proposing a strategy to identify the origin, authenticity, and quality of PJ using HPLC fingerprints, chemometrics, and network pharmacology. METHODS: The chromatographic fingerprint method was established to analyze the origin and authenticity of PJ. Multiple chemometric methods were performed to analyze the fingerprints, including a Hierarchical Cluster Analysis (HCA), Principal Component Analysis (PCA), and Counter Propagation Artificial Neural Network (CP-ANN). Finally, the network pharmacology method was used to construct the "active ingredient-target" network, predict and assist in analyzing potential Qmarkers in PJ. RESULTS: Ward's method was used for the HCA. The results showed that PJ samples from different origins had significant regional differences and could be accurately distinguished from PS. The PCA classification results are consistent with the HCA classification results, further illustrating the model's accuracy. The CP-ANN model can analyze and predict PJ and PS and accurately obtain PJ and PS chemical markers to identify PJ and PS correctly. The network pharmacology of PJ was constructed, and three PJ Q-markers, namely, ginsenoside Ro, ginsenoside Rb1, and chikusetsu saponin Ⅳa, were identified, which lays a foundation for the establishment of PJ quality standards. CONCLUSION: This research provides a feasible platform for the quality evaluation of PJ in the future.

Design, synthesis, and evaluation of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one derivatives: potent BRD4 inhibitors with anti-breast cancer activity.

BRD4 inhibitors have demonstrated promising potential in cancer therapy. However, their therapeutic efficacy in breast cancer varies depending on the breast cancer subtype, particularly in the treatment of TNBC. In this study, we designed and synthesized 94 derivatives of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one to evaluate their inhibitory activities against BRD4. Notably, compound DDT26 exhibited the most potent inhibitory effect on BRD4, with an IC50 value of 0.237 ± 0.093 µM. DDT26 demonstrated significant anti-proliferative activity against both TNBC cell lines and MCF-7 cells. Intriguingly, the phthalazinone moiety of DDT26 mimicked the PAPR1 substrate, resulting in DDT26 displaying a moderate inhibitory effect on PARP1 with an IC50 value of 4.289 ± 1.807 µM. Further, DDT26 was shown to modulate the expression of c-MYC and γ-H2AX, induce DNA damage, inhibit cell migration and colony formation, and arrest the cell cycle at the G1 phase in MCF-7 cells. Our findings present potential lead compounds for the development of potent anti-breast cancer agents targeting BRD4.

Structural modifications of berberine and their binding effects towards polymorphic deoxyribonucleic acid structures: A review.

Berberine (BBR) is a plant derived quaternary benzylisoquinoline alkaloid, which has been widely used in traditional medicines for a long term. It possesses broad pharmacological effects and is widely applied in clinical. In recent years, the anti-tumor effects of BBR have attracted more and more attention of the researchers. The canonical right-handed double-stranded helical deoxyribonucleic acid (B-DNA) and its polymorphs occur under various environmental conditions and are involved in a plethora of genetic instability-related diseases especially tumor. BBR showed differential binding effects towards various polymorphic DNA structures. But its poor lipophilicity and fast metabolism limited its clinical utility. Structural modification of BBR is an effective approach to improve its DNA binding activity and bioavailability in vivo. A large number of studies dedicated to improving the binding affinities of BBR towards different DNA structures have been carried out and achieved tremendous advancements. In this article, the main achievements of BBR derivatives in polymorphic DNA structures binding researches in recent 20 years were reviewed. The structural modification strategy of BBR, the DNA binding effects of its derivatives, and the structure activity relationship (SAR) analysis have also been discussed.