Medicinal Chemistry - Volume 13, Issue 8, 2017

Background: Due to the increasing number of diabetes cases worldwide, there is an international concern to provide even more effective treatments to control this condition. Methods: This review brings together a selection of studies that helped to broaden the comprehension of various biological targets and associated mechanisms involved in type 2 diabetes mellitus. Results: Such studies demonstrated that QSAR techniques and virtual screenings have been successfully employed in drug design projects. Conclusions: Therefore, the main goal of this review is to give the state-of-art for the development of new drugs for the treatment of type 2 diabetes mellitus and to evaluate how computational tools, such as virtual screening and 3D-QSAR, can aid the development of new drugs with reduced adverse side effects.

Background: Fungi performing a wide range of function in soil by secreting low molecular weight compound known as secondary metabolites. S. rolfsii is a soil borne phytopathogenic fungi was used for the production of bioactive compounds. Objective: The present study belongs to evaluate the anticancer potentials of a secondary metabolites isolated from S. rolfsii, their multidrug resistance (MDR), and molecular docking study. Method: (1S,3R,4R,5R,E)-3-(3-(3,4-Dihydroxyphenyl)acryloyloxy)-1,4,5 trihydroxycyclohexanecarboxylic acid (1), or best known as chlorogenic acid, was isolated from the ethyl acetate fraction of crude secondary metabolites produced by the soil borne Fungus Screlotium rolfsii. Structure of chlorogenic acid (1) was confirmed by means of FT-IR, 1H NMR, 13C NMR, and mass spectrometry as well as by melting point. Results: Effect of compound 1 on the reversion of multidrug resistant (MDR) mediated by Pglycoprotein (P-gp) against cancer cells was evaluated with a rhodamine-123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma. Compound 1 was also evaluated for Anti-proliferative effect on the L5178 mouse Tcell lymphoma cell line. Conclusion: Results from the present investigation revealed that compound 1 exhibits excellent MDR reversing effect in a dose-dependent manner against mouse T-lymphoma cell line. Compound 1 also showed anti-proliferative effect on L5178Y mouse T-lymphoma cell line.

Background: 3,3'-Diindolylmethane (DIM) is a condensation product of indole-3-carbinol, a glucosinolate naturally occurring in Brassica genus vegetables. The antiinflammatory properties of DIM through the inhibition of NF-ΚB, as well as its ameliorating effects on glucose tolerance and hyperglicemic states, have been described. A subclinical proinflammatory profile resultant from the interaction of adipocytes and macrophages has been reported in obesity, affecting the insulin signaling pathway, contributing to insulin resistance. Objective: The aim of this study was to evaluate the effect of DIM on proinflammatory cytokines and phosphorylation of IRS-1 pY612 and Akt-1/PKB pT308 in an obesity-induced inflammation model. Methods: Differentiated 3T3-L1 adipocytes were co-cultured with RAW 264.7 macrophages and exposed to 20 μM, 40 μM and 60 μM DIM for 24 h followed by 100 nM insulin for 20 min. MCP-1, IL-6 and TNFα were quantified in the supernatant through individual ELISAs. Adipocyte lysates were used to determine the relative expression of the proinflammatory mediators by qPCR, and the phosphorylation of IRS-1 pY612 and Akt-1/PKB pT308 proteins by western blot analysis. Results: DIM significantly (p<0.05) reduced the production and mRNA expression of MCP-1, IL-6, and TNFα in a DIM concentration dependent manner, concomitantly increasing the abundance of IRS-1 pY612 and Akt-1/PKB pT308. Conclusion: Our results suggest that DIM influences the insulin transduction pathway by exerting an antiinflammatory effect. The potential therapeutic benefits of DIM in the treatment of glucose metabolic disorders deserve further studies.

Objective: Being a kind of post-transcriptional modification (PTCM) in RNA, the 2'-Omethylation modification occurs in the processes of life development and disease formation as well. Accordingly, from the angles of both basic research and drug development, we are facing a challenging problem: given an uncharacterized RNA sequence formed by many nucleotides of A (adenine), C (cytosine), G (guanine), and U (uracil), which one can be of 2-O'-methylation modification, and which one cannot? Unfortunately, so far no computational method whatsoever has been developed to address such a problem. Method: To fill this empty area, we propose a predictor called iRNA-2methyl. It is formed by incorporating a series of sequence-coupled factors into the general PseKNC (pseudo nucleotide composition), followed by fusing 12 basic random forest classifier into four ensemble predictors, with each aimed to identify the cases of A, C, G, and U along the RNA sequence concerned, respectively. Results: Rigorous jackknife cross-validations have indicated that the success rates are very high (>93%). For the convenience of most experimental scientists, a user-friendly web-server for iRNA-2methyl has been established at http://www.jci-bioinfo.cn/iRNA-2methyl, by which users can easily obtain their desired results without the need to go through the complicated mathematical equations involved. Conclusion: The proposed predictor iRNA-2methyl will become a very useful bioinformatics tool for medicinal chemistry, helping to design effective drugs against the diseases related to the 2'-Omethylation modification.

Background: 2,5-Diketopiperazine derivatives are considered to be an important classe of cyclic peptides due to their wide range of biological activities. Objectives: Synthesis of a new series of protected 2,5-diketopiperazine derivatives and evaluation of their in vitro biological activities. Methods: A series of new mono-protected arylidene 2,5-diketopiperazine derivatives 3a-p have been prepared via Claisen-Schmidt condensation of the N,N-diacetyl-diketopiperazine 1 with a series of substituted arylaldehydes. All prepared compounds were characterized by 1D and 2D 1H/13C NMR and ESI-HRMS, and screened for their in vitro acetylcholenesterase, xanthine oxidase and α-amylase inhibition and cytotoxic (HCT-116, MCF-7 and OVCAR-3) activity. Results: Among these compounds, the greatest activity against the α-amylase enzyme (percentage of inhibition (PI)=57.8±1.9%) was obtained for compound 3f bearing a phenoxy moiety. Moreover, the results demonstrated that some arylidene 2,5-diketopiperazines 3 exhibited significant cytotoxic activity against the three cell lines used. The compound 3g (4-PhCH2O.Ph) was found to be the most cytotoxic against the HCT-116, MCF-7 and OVCAR-3 cell lines (PI=83.2±2.4, 89.6±4.9 and 74.4±5.2%, respectively) followed by 3m (2-Br-5-F.Ph) then 3j (4-C2H5-3-NO2.Ph) which displayed a good cytotoxic potential against OVCAR-3 (PI=77.0±2.1 and 71.4±0.9%, respectively). Conclusion: A series of sixteen new arylidene diketopiperazines 3a-p were synthesized via Claisen-Schmidt condensation. Most of the piperazines 3a-p exhibited a good cytotoxic and antidiabetic effects.

Background: Thienopyrimidinone is a newly designed, selective fibroblast growth factor receptor 1 (FGFR1) inhibitor with an excellent anticancer effect. Objective: The goal of the present study was to design and synthesize better FGFR1 inhibitors through modifications of the lead compound thienopyrimidinone. Methods: In the present study, a series of C-2 substituted derivatives of thienopyrimidinone, namely L1-L16, were synthesized, and their inhibitory effects on FGFR1 were evaluated. The anti-proliferative activities of these compounds were assessed by MTT assay. Results: Among the novel derivatives, L11 was found to exert remarkable FGFR1 inhibitory activity (79.93% at 10 μM) and anti-proliferative activity, with IC50 values of 2.1, 2.5, and 3.5 µM in the FGFR1-overexpressing cell lines, H460, HT-1197, and B16F10, respectively. Conclusion: Our newly synthesized thienopyrimidinone derivatives may be candidate FGFR1 inhibitors for future development as novel anticancer agents.

Background: Natural products and their derivatives are widely used to treat cancer and other diseases associated with ROS- and RNS-induced damages. Methods: A series of paramagnetic modified curcumin analogs and 3,5-diarylidene-piperidones (DAP) have been designed, synthesized, and characterized on their anti-proliferative and antioxidant activity. Results: Biological characterization of the new compounds supported the earlier results that incorporation of a nitroxide moiety or its precursor into curcumin or diarylidenylpiperidone (DAP) scaffolds resulted in anti-proliferative effect toward cancerous cell-lines in case of aryl hydroxy and/or methoxy substituent containing derivatives, suggesting their potential for targeted therapeutic applications. In case of basic side chain derivatives, nitroxide incorporation gave unambiguous results, however in tendency the more accessible DAP derivatives had stronger anti-proliferative effect. In most cases, the nitroxide incorporation increased the TEAC value (proton and electron donation capability) of DAP derivatives. Conclusions: Among the compounds synthesized and investigated the spin-labeled curcumin and 3,5-bis(4-hydroxy-3-methoxybenzylidene)piperidin-4-one derivatives were the most effective antiproliferative and antioxidant derivatives.

Background: It was found earlier that compounds combining diazaadamantane and monoterpene moieties possessed promising analgesic activity along with low acute toxicity and the lack of ulcerogenic activity. Objective: In this paper, new structural analogues of the most active compounds were synthesized and evaluated for their analgesic activity. Methods: Their structures were confirmed by various analytical methods, such as 1H and 13C NMR, HRMS. All of them were evaluated for analgesic activity at a dose of 20 mg/kg or less using acetic acid-induced writhing test and hot plate test. Results: Some compounds showed analgesic activity in acetic acid-induced writhing test. One of the synthesized compounds demonstrated high analgesic activity in both tests with 46% effect in acetic acid-induced writhing test and 89% effect in hot plate test. Both structural fragments of this compound did not possess any analgesic effect at a dose of 20 mg/kg. Conclusion: Structure-activity relationships indicated that the most active compound combines fragments of (–)-myrtenal and 6-amino-5,7-dimethyl-1,3-diazaadamantane. Both parts of the molecule are important for demonstrating analgesic activity.

Background: The quinoline ring system is one of the most commonly encountered heterocycles in medicinal chemistry, due to the pharmaceutical and medicinal uses of derivatives containing this ring. These quinoline-based compounds have remarkable biological activity, as they are employed as antimalarial, antibacterial, antifungal, and antitumor agents. The quinoline nucleus can be synthesized by various traditional methods such as the Skraup reaction, Friedlaender synthesis, Combes quinoline synthesis, Larock quinoline synthesis, among others. Methods: The aim of the present work is to synthesize a number of new arylated quninolines having significant antinoceciptive effect through the Suzuki-Miyaura cross coupling reaction using 3- bromoquinoline as a starting material. Results: A number of new quinoline derivatives have been synthesized. Structures of the newly synthesized compounds were confirmed by means of IR, NMR, and mass spectrometry, and by elemental analysis. In addition, the molecular structures of two representative derivatives were determined with the aid of X-ray crystallography. Additionally, the antinociceptive activity of the prepared compounds was evaluated in vivo; results revealed that most of the tested compounds exhibited a dosedependent antinociceptive effect. Conclusion: Prepared compounds were found to exhibit significant antinociceptive activities and could be used as potential analgesic agents. Further work, however, may be required to establish the safety and efficacy of these compounds.

Background: Discovery of novel antiviral agents is essential because viral infection continues to threaten human life globally. Various heterocyclic small molecules have been developed as antiviral agents. The 5,6-dimethoxyindan-1-on nucleus is of considerable interest as this ring is the key constituent in a range of bioactive compounds, both naturally occurring and synthetic, and often of considerable complexity. Objective: The main purpose of this research was to discover and develop small molecule heterocycles as broad-spectrum of antiviral agents. Method: A focused small set of 5,6-dimethoxyindan-1-one analogs (6-8) along with a thiopene derivative (9) was screened for selected viruses (Vaccinia virus - VACA, Human papillomavirus - HPV, Zika virus – ZIKV, Dengue virus - DENV, Measles virus - MV, Poliovirus 3 - PV, Rift Valley fever virus - RVFV, Tacaribe virus - TCRV, Venezuelan equine encephalitis virus - VEEV, Herpes simplex virus 1 -HSV-1 and Human cytomegalovirus - HCMV) using the National Institute of Allergy and Infectious Diseases (NIAID)’s Division of Microbiology and Infectious Diseases (DMID) antiviral screening program. Results: These molecules demonstrated moderate to excellent antiviral activity towards variety of viruses. The 5,6-dimethoxyindan-1-one analog (7) demonstrated high efficacy towards vaccinia virus (EC50: <0.05 μM) and was nearly 232 times more potent than the standard drug Cidofovir (EC50: 11.59 μM) in primary assay whereas it demonstrated moderate activity (EC50: >30.00 μM) in secondary plaque reduction assay. The thiophene analog (9) has shown very good viral inhibition towards several viruses such as Human papillomavirus, Measles virus, Rift Valley fever virus, Tacaribe virus and Herpes simplex virus 1. Conclusion: Our research identified a novel 5,6-dimethoxyindan-1-one analog (compound 7), as a potent antiviral agent for vaccinia virus, and heterocyclic chalcone analog (compound 9) as a broad spectrum antiviral agent.

Background: Both ovarian/breast cancers are the most prevalent hormone-associated gynecological-cancers, where uncontrolled cellular proliferations/genetic-errors are noticed. The cancer-antigen125 (CA125), which we assessed presently is an important biomarker in the early detection/monitoring of this disease-pathogenesis. Methods: Serum/tissue CA125 was measured by solid-phase-Enzyme-linked-immunosorbentassay in women with ovarian/breast tumors of different types (epithelial/non-epithelial; benign/ borderline/ malignant)/stages. Breast-tumor tissues were employed for histoarchitecture/DNAstability (comet) assay. Extensive protein-protein(CA125) interactions were studied by the STRING (Search-Tool-for-the-Retrieval-of-Interacting Genes/Proteins) Bioinformatics-software. Results: Serum CA125 levels were <35 U/ml in 94% of benign epithelial-cases, 35-65 U/ml in 100% of borderline-tumors and >100 U/ml in the 41.17% of patients with malignant-tumors. The malignant epithelial tumor showed significantly higher (>100U/ml) CA125 than the non-epithelial malignant-tumor (<35-65 U/ml). Highly enhanced cellularity/histo-architectural impairment/unstable- DNA-materials/CA125 was found in advanced breast-cancers. The CA125 is highly metabolically interactive, especially with mesothelin impairing cell-cell adhesion and enhancing tissue anti-establishment. Conclusion: CA125 is a predictive-marker in ovarian/breast carcinoma depending on disease nature/stages. CA125, in combination with other tests like mesothelin/estradiol can be of great use in the better diagnosis of this disease. Not only as a detection-marker, has the CA125 played an interactive role in the disease processes. The Bioinformatics study revealed an important role of mesothelin and other mucin like proteins. Early detection and proper diagnosis are important determinants for the greater possibility of the relief from the disease like cancers. Selection of suitable biomarker combinations may increase the better diagnosis of the types and severity of this disease. Our present result has an impact on these aspects.