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Open Journal of Medicinal Chemistry, Volume 02, pp 105-111;

Peptide mimics derived with close structure to peptide have vast utility because they are expected to interfere with biological targets while having superior drug-like properties if compared to peptides. In this work, novel vinyl dipeptides which are different in a double bond between the α-carbon of peptide and C1 of its side chain. Added to that, suitable substituents were selected to harness drug-like properties. The compounds were found to have moderate activities when tested against MCF-7 breast cancer cell line. For instance, the adamantyl analogue 2-(benzoylamino)-3-(2-furyl)-N-(1-adamantyl) propenamide (1c) and the heterocyclic analogue 2-(Benzoylamino)-3-(2-furyl)-N-[2-(5-cyanothia-zol-2-yl)] propenamide (1o) exhibited inhibition potency at 27.4 and 37.8 μM, respectively.
Huan Cui, Weiqiang Tan, Jianshuo Shi,
Open Journal of Medicinal Chemistry, Volume 02, pp 112-118;

Significant progress was achieved in the search of a thrombin receptor antagonist as a novel antithrombotic treatment since the thrombin receptor (protease-activated receptor-1, PAR-1) was cloned 20 years ago. Previous works have shown that it is possible to develop potent thrombin receptor antagonists to compete effectively with the receptor’s internal “tethered” ligand to block platelet activation. Vorapaxar (SCH 530348) from Schering-Plough (now Merck) and atopaxar (E5555) from Eisai have been advanced to human clinical trials. Recently, the pivotal phase III clinical trial results for vorapaxar were published. In this article we review these results plus the phase II results from atopaxar. Several newly described thrombin receptor antagonists from the literature will also be discussed. The phase III results from vorapaxar demonstrated that a thrombin receptor antagonist can achieve efficacy in addition to current standard- of-care in treating atherothrombotic patients, especially those with previous myocardial infarction (MI). However, the increased moderate and severe bleeding, especially intracranial bleeding, point to the limitations of current thrombin receptor antagonists. Future thrombin receptor antagonists that can improve on the efficacy and bleeding profile of current ones should have a promising place in meeting the unmet medical need in treating atherothrombotic patients using current standard therapy.
Ahmed M. El-Morsy, Mohamed S. El-Sayed,
Open Journal of Medicinal Chemistry, Volume 07, pp 1-17;

A new series of 3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives was synthesized. The structures of the new derivatives were confirmed by the spectral data and elemental analyses. The antitumor activity of this series against human breast adenocarcinoma cell line MCF7 was evaluated. Out of twenty new derivatives, ten were revealed mild to moderate activity compared with doxorubicin as a reference antitumor. Among this new series N-(2-chlorophenyl)-2-(3-(methylthio)-4-oxo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)acetamide (13a) was found the most active one with IC50 equal to 23 μM.
Bhagwat Jadhav, R. Kenny, Y. Nivid, , Ramesh Yamgar
Open Journal of Medicinal Chemistry, Volume 06, pp 59-69;

A series of substituted 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides derivatives 5a-5m were synthesized through multi-step reactions. To achieve the synthesis of the desired compounds monobromo and dibromo substituted 2-amino-γ-picoline was reacted with ethyl 2-chloroacetoacetate. The crude ethyl ester subjected to hydrolysis in presence of lithium hydroxide to get 2a and 2b, with imidazo[1,2-a]pyri- dine-3-carboxylic acid to get 3a-3b, on treatment with substituted amines 4a-4g to get desired product 5a-5m in presence of EDCI and HOBt. The substituted imidazo[1,2-a]pyridine-3-carboxamides are characterized by FTIR, 1H-NMR, 13C-NMR and mass spectra. These newly synthesized compounds were tested in vitro for their antimycobacterial activity. The preliminary results of antituberculosis study showed that most of the synthesized compounds 5a-5m demonstrated moderate to good antituberculosis activity. Among the tested compounds 5b, 5d and 5e were found to be the most active with minimum inhibitory concentration (MIC) of 12.5 μg/mL against Mycobacterium tuberculosis (H37 RV strain) ATCC No-27294.
Xing Zheng, Liuying Yu, Xu Yao, Bo Lv, Zehua Yang, Qutong Zheng, Haiying Duan, Chen Song, Hailong Xie
Open Journal of Medicinal Chemistry, Volume 06, pp 51-57;

A novel series of resveratrol derivatives were synthesized according to Wittig-Horner reaction with 3,5-dihydroxybenzyl alcohol or 3,5-dimethoxybenzyl alcohol or 4-hydroxybenzyl alcohol as raw material and the inhibitory activities on breast carcinoma (MDA-MB-231) and gastric carcinoma cell lines (SGC-7901) in vitro were evaluated by the standard methyl thiazole tetrazolium (MTT) method. The result of biological test shows that some of resveratrol derivatives possess stronger anti-cancer activities than 5-FU. Compound 5c shows the strongest activity against breast carcinoma (MDA-MB-231) and gastric carcinoma cell lines (SGC-7901) with IC50 value of 50.19 ± 1.02 μM, 122.68.27 ± 2.04 μM, compared to that IC50 value of 5-FU is 98.59±3.61 μM,156.74±6.16 μM, respectively.
Jinxi Liao, Huimin Cheng, Junting Wan, Panyu Chen, Yingjun Li, , , ,
Open Journal of Medicinal Chemistry, Volume 06, pp 43-50;

Virus nucleoprotein (NP) is an emerging target for drug development for Influenza. We designed benzamide derivatives as new inhibitors of NP that demonstrate good potency in blocking influenza A. Screening revealed that compound 39 was the most potent molecule in the series, exhibiting IC50 values of 0.46 and 0.27 μM in blocking the replication of H3N2 (A/HK/8/68) and (A/WSN/33) influenza A viral strains. The observed inhibition of viral replication correlated well with cytopathic protection. Furthermore, based on computational analysis and fluorescence microscopy, it was determined that compound 39 inhibited nuclear accumulation by targeting influenza A viral nucleoproteins. Finally, the rodent pharmacokinetic profile of compound 32 displayed half-life of greater than 4 hours and bioavailability greater than 20%, suggesting this class of molecules had drug-like properties.
Moiz A. Siddiqui, Amjad Khan, Mehreen Zaka
Open Journal of Medicinal Chemistry, Volume 06, pp 37-42;

Structure Activity Relationship forms the basis of Rational Drug Design in the circles of pharmaceutical and medicinal chemistry. Appropriate knowledge of functional outcomes of structural modifications is crucial in conferring desired pharmacological properties to a chemical compound. Amiodarone is a classical antiarrythmic agent with a long list of adverse effects. This article attempts to review the structure activity relationship of some of the homologues of amiodarone in order to determine the most clinically desirable molecule.
Mahmoud S. Bashandy, Fatma A. Mohamed, , Mahmoud B. Sheier, Ahmed H. Bedair
Open Journal of Medicinal Chemistry, Volume 06, pp 18-35;

This article describes the synthesis of some novel coumarin compounds to use as acid dyes by using compounds 1 - 4 as starting materials, which were prepared by interaction of 2-hydroxybenzaldehyde with ethyl 3-oxobutanoate, diethylmalonate, 4-nitrobenzenediazonium chloride and 4-sulfobenzenediazonium chloride, respectively. Compound 1 reacted with bromine and 2-cyanoacetohydrazide to give phenacyl bromide derivative 5 and 2-cyanoacetohydrazone derivative 6, respectively. Coupling of compound 6 with equimolar amount of 2-sulfo-4-((4-sulfophenyl) diazenyl)benzenediazonium chloride gave coumarin acid dye 8. Phenacyl bromide derivative 5 re-acted with potassium cyanide in refluxing ethanol to produce compound 7, which on coupling with equimolar amount of 8-hydroxy-6-sulfonaphthalene-2-diazonium chloride and 8-hydroxy-3,6-disulfonaphthalene-1-diazonium chloride gave coumarin acid dyes 9 and 10, respectively. Interaction of compound 2 with 2-amino-5-((4-sulfophenyl)diazenyl)benzenesulfonic acid, benzene-1,4-diamine and 3,3’-dimethoxy-[1,1’-biphenyl]-4,4’-diamine in refluxing ethanol afforded compounds 11, 12 and 14, respectively. Diazonium sulphate of compounds 12 and 14 coupling with 4-amino-5-hydroxynaphthalene-2,7-disulfonic acid gave compounds 13 and 15, respectively. Cyclocondensation of compound 3 with ethyl 3-oxobutanoate, diethyl malonate and malononitrile afforded derivatives of 3-acetyl-2H-chromen-2-one 16, ethyl 2-oxo-2H-chromene-3-carboxylate 17 and 2-imino-2H-chromene-3-carbonitrile 18, respectively. Reaction of sodium benzenesulfonate derivative 4 with ethyl 3-oxobutanoate and hydrazine hydrate gave compounds 19 and 20, respectively. The structures of the newly synthesized compounds were confirmed by elemental analysis, UV/ VIS, IR, 1H NMR and Ms spectral data. The suitability of the prepared dyestuffs for dyeing of wool and silk fabrics has been investigated. The dyed fabric shows good light fastness, very good rubbing, perspiration, washing and excellent sublimation fastness. These dyes have been color shade from blue to violet with very good depth and levelness on fabrics. The dye bath exhaustion and fixation on fabric has been found to be very good.
, Venkatesh Chelvam, Mahalingam Sakkarapalayam, Guo Li, Pedro Sanchez-Cruz, Natasha S. Piñero, ,
Open Journal of Medicinal Chemistry, Volume 06, pp 1-17;

Almost all cells are easily killed by exposure to potent oxidants. Indeed, major pathogen defense mechanisms in both animal and plant kingdoms involve production of an oxidative burst, where host defense cells show an invading pathogen with reactive oxygen species (ROS). Although cancer cells can be similarly killed by ROS, development of oxidant-producing chemotherapies has been limited by their inherent nonspecificity and potential toxicity to healthy cells. In this paper, we describe the targeting of an ROS-generating molecule selectively to tumor cells using folate as the tumor-targeting ligand. For this purpose, we exploit the ability of 9,10-phenanthraquinone (PHQ) to enhance the continuous generation of H2O2 in the presence of ascorbic acid to establish a con-stitutive source of ROS within the tumor mass. We report here that incubation of folate receptor-expressing KB cells in culture with folate-PHQ plus ascorbate results in the death of the cancer cells with an IC50 of ~10 nM (folate-PHQ). We also demonstrate that a cleavable spacer linking folate to PHQ is significantly inferior to a noncleavable spacer, in contrast to most other folate-targeted therapeutic agents. Unfortunately, no evidence for folate-PHQ mediated tumor regression in murine tumor models is obtained, suggesting that unanticipated impediments to generation of cytotoxic quantities of ROS in vivo are encountered. Possible mechanisms and potential solutions to these unanticipated results are offered.
Gabriela Souza Fernandes, Michelle Bueno De Moura Pereira, Ana Cláudia Barbosa Marinho, Brisa Machado, Ana Carla Moreira, Matheus Puggina de Freitas, Karen Luise Lang, João Eustáquio Antunes
Open Journal of Medicinal Chemistry, Volume 05, pp 106-115;

In silico pharmacokinetics studies can aid the search for molecules with potential ability to be drug candidates. In this paper, a number of quinazoline candidates for epidermal growth factor receptor inhibitors—EGFR, important targets for the treatment of cancer, are computationally analyzed. The literature described that 69 quinazoline molecules were synthesized and the respective half maximum inhibitory concentrations (IC50) were obtained. A bilinear parabolic model was built to investigate the druglikeness by correlating the corresponding lipophilicities, which can be represented by the ideal Log P , with the optimal biological activity in terms of pIC50 values. Structural characteristics leading to improved pharmacokinetics parameters were then analyzed. Compound 56 exhibited the lowest IC50 and, therefore, it had the highest ability to inhibit the EGFR. In the present work, the most potent inhibitor 56 is not calculated to be the most promising drug candidate, since it’s out of the parabolic model obtained due to a Log P above 5, which is not within the expected optimum range. Finally, this work is an example of computational prediction that an experimentally, highly active EGFR inhibitor can be unsuccessful as drug candidate because of pitfalls in pharmacokinetics parameters.
Ya Liu, Yi Liu, Hongfei Chen, Xu Yao, Yan Xiao, Xianliang Zeng, Qutong Zheng, Yun Wei, Chen Song, Yinxiang Zhang, et al.
Open Journal of Medicinal Chemistry, Volume 05, pp 97-105;

Resveratrol, a naturally derived stilbene that exists in various foods and beverages, has attracted extensive exploration due to its multiple biological activities, such as anticancer, antioxidant, cardiovascular protection, anti-inflammatory, antiviral, chemopreventive effect, neuroprotective effect, immunomodulation and so on. However, owing to its poor oral bioavailability, the application of resveratrol is greatly restricted. Because of that, a large amount of efforts had been made by researchers on designing its derivatives to obtain compounds with improved efficiency and low toxicity for developing more active drugs for clinical application. In this report, we review the current development of studying on resveratrol derivatives including their properties and activities. Additionally, this article also presents the synthetic routes of correlative resveratrol derivatives.
M. T. Sarg, M. M. Koraa, A. H. Bayoumi, S. M. Abd El Gilil
Open Journal of Medicinal Chemistry, Volume 05, pp 49-96;

We herein disclose a series of novel pyrrole derivatives as well as fused pyrrolopyridines 6a,b and 7a,b, pyrrolopyrazoles 8a, b, pyrrolo[2,3-d]pyrimidine derivatives 10a-d, 12a,b, 14a,b, 18a,b, 20a,b, 21a,b, 22a,b, 23a,b, 24a,b, 31a,b, 36a,b, 40a,b, pyrrolo[1,2,6]thiadiazine derivatives 19a,b, pyrrolotriazolopyrimidines 25a,b, 26a,b, 27a,b and 28a,b, pyrrolo[2,3-d][1,2,3]triazine derivatives 32a,b and pyrrolo[2,3-d][1,3]oxazine derivatives 39a,b as novel compounds. All compounds were evaluated for their anti-inflammatory, analgesic (compared to the reference drug Indomethacin) and antimicrobial activities (compared to the reference drug Ampicillin and Fluconazole). Compounds 4d, 5b-d, 6a,b, 9c,d, 10d, 12ab, 13b, 19a,b, 21b, 23b, 31a,b, 38b and 40a were found to be the most active anti-inflammatory drugs exhibiting potency ranging from 1 - 1.01 compared to the reference drug indomethacin. In addition to docking study of these highly active twenty compounds against the active site of cyclooxygenase-2 enzyme (COX-2), among the tested compounds, compounds 5d, 9d, 11b, 12a, 13b and 32a showed multiple activities; anti-inflammatory, analgesic and anti-bacterial activities.
M. Manimaran, A. Ganapathi, T. Balasankar
Open Journal of Medicinal Chemistry, Volume 05, pp 33-47;

To exploit the potential biological activities of azabicyclic based, seven 2r, 4c-diaryl-3-azabicyclo [3.3.1] nonan-9-one-2’-thienoyl hydrazone were synthesized. The structural elucidation and stereochemistry of these compound assigned by FT-IR, 1H, 13C and 2D NMR spectral data. The Structural Activity Relationship (SAR) of the target compounds were examined for their in vitro anti-proliferative, antioxidant and antimicrobial activities. The initial screen was treated against human liver cancer cell lines (HepG2) with IC50 values determined by MTT assay. Fluoro substitution at para position of phenyl ring compound 12 showed more antiproliferative activity against HepG2 at half maximum inhibitory concentration (IC50 = 3.76 μg/mL) than other target hydrazones. The mechanism of the antitumor action of active compound 12 was investigated through Hoechst stain 33342 analyses. It indicated that the compound inhibited HepG2 cancer cells proliferation by triggering apoptotic cell death. The Free radical scavenging activity of all synthesized compounds were evaluated with , and radicals. The compounds 11 (IC50 rang 3.78 - 4.31 μg/mL) and 15 (IC50 rang 4.61 - 5.16 μg/mL) were exhibited higher free radical scavenging activity than standard BHT drug. Besides, all the target compounds were screened for their in vitro antibacterial and antifungal activity against a spectrum of microbial organisms by using twofold dilution method. These studies proved that halogen substituted compounds 12, 13 and 14 were showed excellent inhibitory potency at lowest minimum inhibitory concentration (MIC) range of 6.25 - 25.5 μg/mL. Nevertheless, multiple mechanisms regulating the antioxidant and anticancer effects of the hybrid molecules need to be further investigations.
Fernández Ruocco María Julieta, Siri Macarena, Igartúa Daniela, Prieto María Jimena, Alonso Silvia Del Valle, Chiaramoni Nadia Silvia
Open Journal of Medicinal Chemistry, Volume 03, pp 31-39;

Polymerized liposomes encapsulating L-tryptophan were studied with the aim to characterize them as drug delivery systems for the treatment of several metabolic diseases that need an increased systemic L-tryptophan concentration. polymerized liposomes were obtained by UV irradiation of vesicles containing 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC8,9PC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) in a 1:1 molar ratio, in the presence of 10 and 50 mol% of L-tryptophan (respect to total lipid concentration). Polymerization efficiency was studied spectrophotometrically. Also, bilayer packing at the polar head region was followed with the Merocyanine 540 (MC540) and specific interactions in the lipopolymers were studied by FTIR. High L-tryptophan concentrations (50 mol% respect to total lipid concentration) induced a higher amount of six- and nine-unit polymers. This phenomenon was induced because the L-tryptophan located outside the lipid membrane was included in it during the polymerization process and was thus responsible for the better accommodate of the polar head region. This was not possible with the lower amount of L-tryptophan (10 mol%). The stability of lipopolymers with different amounts of L-tryptophan was studied through release profiles. Polymerized liposomes with 50 mol% of L-tryptophan were able to retain around 80% of the amino acid after 24 hours, whereas those with 10 mol % of the amino acid were able to retain 20%. The metabolic activity of the Caco-2 cell line was also studied. Cytotoxic effects were low in the presence of polymerized liposomes, rendering a maximum percentage of cell death of 30%. In summary, this work stresses the relevance of nonspecific drug-polymerized membrane binding on L-tryptophan pharmacological interaction with possible pharmaceutical applications in liposomal drug delivery. Moreover, the absence of significant cytotoxic effects allows the system proposed to be applied in human health.
Zhongqin Li, Ruizhang Guan, Hongwei Liu
Open Journal of Medicinal Chemistry, Volume 03, pp 26-30;

A new reversed-phase high performance liquid chromatography method was developed to quantitate the activity of xanthine oxidase involved in milk fat globule membrane with xanthine as the substrate and the separation of product (uric acid). The increment of uric acid in the reaction system was used to calculate the total activity of XO. The optimized assay conditions, linearity of detection, recovery of uric acid and chromatogram were developed in text, indicating this method is simple, rapid and efficient. It is an alternative potential method for the determination of the activity of XO in milk.
, , Mark Gardner, , Stephen M. Shaw, , , Caroline Smith-Burchnell, Rob Webster, Satish Dayal
Open Journal of Medicinal Chemistry, Volume 03, pp 16-25;

A high throughput screen of the Pfizer compound collection was carried out using a hepatitis C virus (HCV) genotype 1b subgenomic replicon cell line. Those confirmed hits that demonstrated broad spectrum activity without overt cytotoxicity were further evaluated, leading to the identification of a series of pyrrolopyridines with excellent antiviral activity in a fully infectious HCV cell-based assay and pharmacokinetic properties.
Rokaya Mouhibi, , Khalid El Akri, Na^ima Hanafi
Open Journal of Medicinal Chemistry, Volume 03, pp 7-15;

Quantitative structure–activity relationship (QSAR) models were developed to predict for CCR5 binding affinity of substituted 1-(3, 3-diphenylpropyl)-piperidinyl amides and ureas using multiple linear regression (MLR) and artificial neural network (ANN) techniques. A model with four descriptors, including Hydrogen-bonding donors HBD(R7), the partition coefficient between n-octanol and water logP and logP(R1) and Molecular weight MW(R7), showed good statistics both in the regression and artificial neural network with a configuration of (4-3-1) by using Bayesian and Leven-berg-Marquardt Methods. Comparison of the descriptor’s contribution obtained in MLR and ANN analysis shows that the contribution of some of the descriptors to activity may be non-linear.
Ping Li, Yunzhi Pan, Alice S. S. Li, Aijuan Sun, Jia Zhang, H. L. Gao, Pierre Sirois,
Open Journal of Medicinal Chemistry, Volume 03, pp 1-6;

Duchenne Muscular Dystrophy (DMD) is a severe childhood form of muscular dystrophy. Both the severe form and its milder form of Becker Muscular Dystrophy (BMD) are caused by the mutation of dystrophin gene. Different from some other genetic diseases such as hemophilia that can be treated by replacement therapy, there is no effective therapy for muscular dystrophy in conventional medication. Gene editing technology from the recently developed engineered nucleases such as TALENs has been successfully employed in genome modification of a variety of species, and will be applied in gene therapy of selected human diseases. The genetic basis of DMD and BMD indicates that DMD is a good target for gene therapy through returning the reading frame of dystrophin gene. Gene therapy strategies described here may apply to many other genetic diseases. Wider application of TALENs in gene therapy have the potential to dramatically prolong the lifespan of individuals with genetic diseases.
Xiaolong Shi, Saiyang Zhang, Jianghao Wang, Tingyu Li, Junju Liu, Yi Hou, Lei Liu, Dongjun Fu, Haiwei Xu, Hongmin Hongmin, et al.
Open Journal of Medicinal Chemistry, Volume 05, pp 23-31;

Petasin is a potential antitumor against human neuroblastoma cell SK-N-SH by inhibiting the ERK1/2 phosphorylation. In view of its great activity and new antiproliferative mechanisms, a series of petasin derivatives were designed and synthesized, which showed great antiproliferative activity. Among them compounds 1h and 1f were more effective against SK-N-SH cells than petasin with the IC50 values of 0.87 and 2.63 μM, respectively.
Open Journal of Medicinal Chemistry, Volume 05, pp 9-22;

Phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and phenyl 4-(2-oxoimidazolidin- 1-yl)benzenesulfonamides (PIB-SAs) are new, potent combretastatin A-4 (CA-4) analogs designed on the basis of their common phenyl 2-imidazolidone moiety. This phenyl 2-imidazolidone group is a bioisosteric equivalent of the trimethoxyphenyl group also found in colchicine, podophyllotoxin and several other ligands of the colchicine-binding site (C-BS). In this study, we investigate the interactions involved in the binding of PIB-SO and PIB-SA into the C-BS. We describe three distinct pockets (I, II, and III) as key structural elements involved in the interactions between the C-BS and PIB-SOs as well as PIB-SAs. We show that PIB-SOs and PIB-SAs adopt 4 and 3 distinct binding conformations, respectively, within the C-BS. The binding conformations I and IV are common to most PIB-SOs and PIB-SAs exhibiting high affinity for the C-BS and high cytocidal potency. In addition, binding conformation I is the main conformation adopted by PIB-SOs, PIB-SAs, T138067, ABT-751, colchicine and CA-4. We also observe that the sulfonate and the sulfonamide moieties of PIB-SOs and PIB-SAs are bioisosteric equivalents. Interestingly, we further find that a large portion of the phenyl 2-imidazolidinone moiety in these analogs does not bind to pocket I unlike the trimethoxyphenyl moiety found in several antimicrotubule agents such as colchicine, CA-4 and podophyllotoxin, suggesting that the phenyl 2-imidazolidinone group may represent a new haptophoric moiety useful for the design of new C-BS inhibitors mimicking the tropolone and the methoxylated phenolic moieties of colchicine and CA-4, respectively.
, Suzuka Tsuboi, , , Yonchol Shin
Open Journal of Medicinal Chemistry, Volume 05, pp 1-8;

In this study, we prepared a peptide nucleic acid (PNA) against the gene coding for the human alpha 1 chain of type I collagen. This PNA was incorporated into normal human fibroblast cells by electroporation, leading to a decrease in the mRNA level of the gene. Furthermore, mRNA for the alpha 2 chain of type I collagen was also reduced. The production of collagen protein exhibited a similar profile to the changes in mRNA. These results indicate that PNA targeting COL1A1 is effective as an antigene reagent, and opens the possibility of future clinical applications in fibroproliferative disorders.
Márcio Shigueaki Mito, Cristiane Vizioli de Castro, ,
Open Journal of Medicinal Chemistry, Volume 04, pp 87-95;

The action mechanism of ranolazine, an antiangina drug, could be at least partly metabolic, including inhibition of fatty acid oxidation and stimulation of glucose utilization in the heart. The purpose of the present work was to investigate if ranolazine affects hepatic carbohydrate metabolism. For this purpose, the hemoglobin-free isolated perfused rat liver was used as the experimental system. Ranolazine increased glycolysis and glycogenolysis and decreased gluconeogenesis. These effects were accompanied by an inhibition of oxygen consumption. The drug also changed the redox state of the NAD+-NADH couple. For the cytosol, increased NADH/NAD+ ratios were observed both under glycolytic conditions as well as under gluconeogenic conditions. For the mitochondria, increased NADH/NAD+ ratios were found in the present work in the absence of exogenous fatty acids in contrast with the previous observation of a decreasing effect when the liver was actively oxidizing exogenous oleate. It seems likely that ranolazine inhibits gluconeogenesis and increases glycolysis in consequence of its inhibitory actions on energy metabolism and fatty acid oxidation and by deviating reducing equivalents in favour of its own biotransformation. This is in line with the earlier postulates that ranolazine diminishes fatty acid oxidation, shifting the energy source from fatty acids to glucose.
Open Journal of Medicinal Chemistry, Volume 04, pp 79-86;

In this paper, we report the design and moleculardocking study of analogues of antimycin A3 as inhibitors of anti-apoptotic Bcl-2 of breast cancer. Twenty designed compounds and the original antimycin A3 were docked based on their interaction with breast tumor receptor binding target Bcl-2. The docking resulted in the five top-ranked compounds, namely, compounds 11, 14, 15, 16, and 20, which have a lower G binding energy, better affinity and stronger hydrogen bonding interactions to the active site of Bcl-2 than antimycin A3. Among those five top-ranked compounds, analogue compounds 11 and 14, which have an 18-membered tetralactone core and 18-membered tetraol core, respectively, exhibited the strongest hydrogen bond interaction, formed high stability conformation, and demonstrated the greatest inhibitory activity on the catalytic site of Bcl-2.
Elena E. Dubinina, Irina V. Churilova, , Liudmila V. Zhuravleva
Open Journal of Medicinal Chemistry, Volume 04, pp 70-78;

Recsod® has been used for treating epilepsy and ophthalmological disease. Oxidative stress has been demonstrated to be a pathogenic chain of these diseases. Parameters of pro- and antioxidant systems were studied in all the patients treated. Recsod® drug was shown to produce positive effect in all the patients. Improvement of patients’ clinical condition correlated with an increase in antioxidant activities. Antioxidants, in particular, the recombinant human SOD drug, proved to be effective in treatment of some neurological and ophthalmological diseases.
, A. C. Scalabrini, T. S. Marinho, C. R. K. Antonietto,
Open Journal of Medicinal Chemistry, Volume 04, pp 61-69;

Background: The production of endothelial-derived factors induces either vasoconstriction or vasodilation; nitric oxide (NO) is the most distinguished relaxing factor. Endothelial dysfunction is associated with hypertension. The partial loss in the NO-promoted vasodilation is due to its decreased bioavailability and/or to an activity reduction of endothelium NO synthase (eNOS). Reactive oxygen species (ROS), present in oxidative stress, seize NO and diminish its bioavailability. Transresveratrol (RESV) has been proved to increase NO and eNOS levels. Thus, RESV could be capable of improving NO dependent vascular relaxation on aortic rings isolated from treated 2K-1C animals through ROS damage reduction. Aim: Evaluate the effects of RESV treatment on the relaxation of aortic rings isolated from treated 2K-1C rats while focusing on the effects of the treatment on systolic blood pressure. Methods: Male Wistar rats (180 g) were grouped: two 2K-1C and two Sham groups, one of each was treated with RESV (20 mg/kg, gavage) dissolved in Tween 80 and one of each was treated with water plus Tween 80 (control) for six weeks. The rats had their systolic blood pressure (SBP) measured before and after the treatments. Vascular reactivity studies were conducted in order to observe and compare acetylcholine (ACh)-induced relaxations in the presence and absence of the NOS inhibitor L-NAME (10-4 mol/L). Results: SBP for 2K-1C was significantly reduced in the treated group (179.13 ± 4.90 mmHg, n = 23) when compared to the untreated group (196.66 ± 6.06 mmHg, n = 15, p
Marwa Taha Mostafa Sarg, Shereen Said El-Shaer
Open Journal of Medicinal Chemistry, Volume 04, pp 39-60;

6-aminouracil 1 was utilized to introduce different heterocyclic rings at C-6 position through various synthetic strategies. The synthesized compounds bear rings that are either directly attached to the uracil back bone as in compounds 6, 12a-c and 15, or attached through an amino bridge as compounds 3a-c, 5a, b, 7a, b, 9 and 10, or through an imino bridge as compound 18. Also, compounds 4, 8, 11a-c, 14, 16 and 17 bearing biologically active side chains were synthesized. In addition to, compounds 13, 19, 20, 21 and 22 bear fused rings to the uracil backbone. All synthesized compounds were evaluated for their anticancer activity against prostate PC3 cell line using in-vitro sulforhodamine-B (SRB) method, from which compounds 3a, c, 4, 5a, b, 6, 7a, b, 11a-c, 12a, b, 17 and 20 were the most active. These active compounds were further evaluated for their ability to inhibit cathepsin B enzyme by using enzyme-linked immunosorbent assay, which revealed that compounds 5a, b, 7a, 11a, 12a and 17 exhibited more than 50% inhibition of cathepsin B. Among which the phenyl thiourea derivative 17 was the most active exhibiting 82.3% inhibition, while the reference doxorubicin exerted 18.7% inhibition.
Aisha Youssif Hassan Helali, Marwa Taha Mostafa Sarg, Makarem Mohamed Said Koraa, Mona Said Fathy El-Zoghbi
Open Journal of Medicinal Chemistry, Volume 04, pp 12-37;

Quinolino[2,1-b]quinazolines 3 and 4, pyrrolo[2,1-b]quinazoline 5 and various substituted 2-(4-chlorostyryl)quinazoline derivatives including: 4-amino derivative 8, 4-hydrazino derivative 9, thiourea derivative 10, thiosemicarbazide derivative 19, 4-benzylidene hydrazinyl derivative 21, 4-amino thiazolidene derivatives 11, 12, 13, 22, imidazoquinazolines 15, 16, quinazolinium chloride 14, triazino[4,3-c]quinazolines 17, 18, tetrazino[1,6-c]quinazoline 20, 4-amino azetidinyl derivative 23, triazolo[4,3-c]quinazoline 24, 4-amino substituted quinazolines 25, 26, 27, 29 and quinazolino quinazoline 28 were synthesized through different chemical reactions. The obtained compounds were evaluated for their in vitro antitumor activity against HEPG2 and MCF-7 cell lines compared to the reference drug (doxorubicin). Compounds 18, 19, 20, 23 and 24 were found to be the most active against both cell lines exhibiting IC50 values ranging from 10.82 - 29.46 μM/L and 7.09 - 31.85 μM/L against Hep-G2 and MCF-7 cell lines, respectively, in addition to docking study of these five compounds against thymidylate synthase and dihydrofolate reductase enzymes active sites.
Christian Vélez, Beatriz Zayas,
Open Journal of Medicinal Chemistry, Volume 04, pp 1-11;

Etoposide is a chemotherapy drug derived from the natural lignin podophyllotoxin. Our novel generated Aza-podophyllotoxin compounds (AZP 8a & AZP 9a) are analogues of podophyllotoxin and were previously screened for anti-cancer activity through the NCI 60 cell line screening panel showing activity on various cell types including colon cancer. This study expands the toxicological screening by studying apoptosis and various hallmark events as part of the mechanism of action of these compounds on colon cancer cells. The COLO 205 cell line was selected and exposed to AZP to determine the IC50 doses at 24 hours treatment. Apoptosis hallmark events such as migration of phosphatidylserine (PS) to the cell membrane, DNA fragmentation, cell cycle effects, mitochondrial membrane permeabilization and caspase activation were included. Experiments were performed in triplicates for all tested compounds including AZP 8a, AZP 9a, camptothecin as positive control and vehicle as negative control. Our results present contrasting apoptotic activity between the experimental compounds. Compound 8a presented migration of PS (annexin V assay), DNA fragmentation and cell cycle arrest at S phase. Compound 9a presented PS migration with fragmented DNA, cell cycle arrest at S phase, mitochondrial membrane permeabilization and activation of caspase 3, 8 and 9. Compound 8a without the oxygen atoms in ring A appears to cause effects similarly to autophagy as induced by etoposide, a cancer drug analogue of our heterocyclic compounds. Compound 9a with the oxygen atoms in expanded ring A presented induction of cell death following activation of a classical apoptosis pathway. Our results suggest that minor structural differences among these AZP can account for the difference in biological response and cancer cell toxicity.
María Cristina Caterina, Isabel A. Perillo, Ximena Villalonga, Nicolás Amiano, Cristian Payés, Mercedes L. Sanchez,
Open Journal of Medicinal Chemistry, Volume 03, pp 121-127;

A new green synthesis and anti-tumor activity of the series of bis (3-arylimidazolidinyl-1) methanes 1 - 6 are described. The compounds were synthesized from the corresponding N-arylethylenediamine and trioxane as sources of formaldehyde and the reactions were performed in heterogeneous phase catalyzed by an acidic ion-exchange resin (Amberlyst 15). The compounds were tested with the Sulforhodamine B assay according to the protocol of the National Cancer Institute for several cell lines. The results were expressed as percentage inhibition of growth cell in comparison with the full growth of the cells without treatment. Cytotoxicity on normal cells using the Annexing-PI staining and flow cytometry has been evaluated. The parent compound, bis(3-phenylimidazolidinyl-1)methane 1 and the monohalogenated derivatives 4-chlorophenyl 3 and 3-bromophenyl 5 showed antineoplastic activity, 60%, 82% and 89% inhibition growth cell respectively on the human colon cell line (HCT116). The 4-tolyl derivative 6 presented inhibitory activity (73% inhibition of growth cell) on human lung adenocarcinoma cell line (A549) and 62% on human mammary cell line MCF-7.
Khalid El Akri, Rokaya Mouhibi, , Na^ima Hanafi, Moulay Abdellah Bahlaoui
Open Journal of Medicinal Chemistry, Volume 03, pp 100-120;

A series of N-carbonyl-functionalized ureas, carbamates and thiocarbamates derivatives (or N-Chloro sulfonyl isocyanate “N-CSI”) were involved in linear and nonlinear physicochemical quantitative structure-activity relationship “QSAR” analysis to find out the structural keys to control the inhibition against Sterol O-Acyl-Transferase-1 “SOAT-1”. The results indicate the important effects of geometrical and chemical descriptors on the inhibitory activity of SOAT-1. The molecules were also screened for three-dimensional molecular docking on the crystal structure of ACAT-1 (1WL5 for ACAT-1, PDB). A comparison between 2D-QSAR and 3D molecular docking studies shows that the latter confirm the first results and represent a good prediction of the chemical and physical nature of interactions between our drug molecules and enzyme SOAT-1.
Kazuhiro Ooka, Atsushi Fukumoto, Tomoe Yamanaka, Kanako Shimada, Ryo Ishihara, Yojiro Anzai, Fumio Kato
Open Journal of Medicinal Chemistry, Volume 03, pp 93-99;

Piericidin A1, 3’-rhamnopiericidin A1, and a novel compound piericidin E, a new quorum-sensing (QS) inhibitor against Chromobacterium violaceum CV026, were isolated from the culture broth of Streptomyces sp. QS is well known as a microbial signaling system and controls certain types of gene expression resulting in bioluminescence, biofilm formation, swarming motility, antibiotic biosynthesis, and virulence factor production. C. violaceum CV026 is commonly used to determine qualitative and quantitative QS activity. The structures of piericidin derivatives were characterized, and their QS activities were determined.
Chunxia Chen, Minghui Lu, Zhihui Liu, Junting Wan, Zhengchao Tu, ,
Open Journal of Medicinal Chemistry, Volume 03, pp 128-135;

A series of 2-amino-4H-pyran-3-carbonitrile derivatives were designed and synthesized. Their antitubercular activities were evaluated against autoluminescent M. tuberculosis H37Ra and standard strain M. tuberculosis H37Rv. No obvious antitubercular activities could be observed (MIC > 10 ug/mL). The results are in sharp contrast with the previously reported data.
, Sanjay B. Bari
Open Journal of Medicinal Chemistry, Volume 03, pp 87-92;

The glyceride ester derivatives 6a and 6b were prepared by reacting 1,2,3-trihydroxy propane 1,3-dipalmitate/stearate with (S)-naproxen as potential prodrugs. The synthesis was achieved successfully with the aid of N,N’-dicyclohexyl- carbodiimide. These prodrugs were evaluated for anti inflammatory, analgesic and gastroprotective activity. It was found that prodrugs 6a and 6b showed less irritation to gastric mucosa as indicated by ulcer index. The synthesized glyceride esters were found to possess good pharmacological profile as shown by results of anti inflammatory and analgesic activity. The aqueous studies were performed in order to ensure the release of prodrugs. Both prodrugs were found to stable at acidic pH while undergoes hydrolysis at pH 7.4. These findings suggest that the glyceride prodrugs 6a and 6b might be used as potential biolabile derivatives.
Kun-I Lin, Li-Wu Chiang, Cheng-Tse Pan, Ho-Lien Huang, Yuan-Hsiao Su, Shui-Tein Chen, ,
Open Journal of Medicinal Chemistry, Volume 03, pp 74-86;

6-azidogalactosyl imidate has been used as a donor to generate 1-(4-aminobutyl)-6-aminogalactose, 6-aminothiotolyl- glycosides of disaccharide, trisaccharide and tetrasaccharide that incorporates 6-azido group and 1-(4-tolyl)thio group. Trisaccharide and tetrasaccharide were obtained from lactosyl-based acceptor. The anomeric 1-(4-tolyl)thio group could be used to conjugate with sphingosine analogs to provide the alpha-Gal Sph analogs for library extension from the azido group.
Nihad Abdel-Monem, , E. S. H. El Ashry, ,
Open Journal of Medicinal Chemistry, Volume 03, pp 60-73;

Marine derived fungi are considered as a promising source of novel drugs due to their biodiversity and consequent chemo-diversity. Although marine microorganisms especially fungi are not well defined taxonomically, making this a promising frontier for the discovery of new medicines. This study focused on marine derived fungi as a model for bioactive exploration for new entities with anti-inflammatory and antioxidant capacity. Three in-vitro assays were used to investigate the bioactive antioxidant potentiality of fungal extracts. Thiobarbituric acid (TBARS),α,α-Diphenyl-β- picrylhydrazyl (DPPH) and NO assay are based on their total phenolic and flavonoid content of each extract group. Ch. globosum recorded the highest antioxidant activity (92.82%) in TBARS assay, while G. dankaliensis came first by recording 59.28% in DPPH assay in comparison with ascorbic acid (61.83%). In NO inhibition assay, N. oryzae showed 49.3% comparing with ascorbic acid (73.12%). From the preliminary result of our extracts, we can consider the marine derived fungi extracts as promising antioxidant and anti-inflammatory drug candidate.
, Wei-Ting Chen, Shu-Fan Tien, Ho-Lien Huang, , Kun-I Lin,
Open Journal of Medicinal Chemistry, Volume 03, pp 55-59;

Four a-galactosyl phytosphingosine 2,6’-diamide analogs were prepared from 2,6’-diamino a-galactosylphytosphingosine and the aromatic-bearing carboxylic acids. After purification with High Performance Liquid Chromatography, a flowcytometry for the four compounds for stimulation of human Va24+/Vb11+ NKT cell populations was carried out. Additional keto groups on the acyl chains of the 2,6’-diamide compound was associated with the enhanced stimulating effect.
S. Sreenivasa,
Open Journal of Medicinal Chemistry, Volume 03, pp 50-54;

In the present investigation, series of Bis (heterocycle)s bearing pyrazoline in combination of the imidazole derivatives have been synthesized via 1,3-dipolar cycloaddition reactions of N-(nitrobenzyl)-imidazole nitrile imines with different dipolarophiles. All the newly synthesized compounds were characterized and screened for analgesic-anti-inflammatory activities and were compared with the standard drugs. The compounds exhibited excellent anti-inflammatory and analgesic activities. Out of the compounds studied 4b, 4d and 4g compounds shown statistically significant activity comparable to the standard drugs Ibuprofen and Aspirin at the same dose.
Open Journal of Medicinal Chemistry, Volume 03, pp 41-49;

G-quadruplexes (G4) are non-canonical DNA structures assumed by guanine rich sequences. G4 are stabilized by the presence of cations and are characterized by a high degree of structural polymorphism with different patterns of groove, loop arrangement, strand orientations and stoichiometry. G-rich sequences are over-represented in the promoter regions of many oncogenes as well as at human telomeres, d(TTAGGG) repeats, ranging in size from 3 to 15 kb, involved in protecting chromosomal ends. A specialized enzyme, called telomerase, provides a telomere maintenance mechanism by elongating the end of the G-strand and it is activated in the majority of cancer cells. Therefore there are two general strategies of telomerase targeting in cancer treatment. One is a direct targeting of telomerase to cause its inhibition; the other one is the use of G4 stabilizers which block telomerase access to telomere, thus causing an indirect enzyme inhibition. Here, we evaluated the molecular recognition of some phenanthroline-based ligands against four different experimental models of the human telomeric sequence d[AG3(T2AG3)3] by means of docking simulations. Our theoretical analysis was able to reproduce the experimental affinity measurements, with a linear squared correlation factor r2 equal to 0.719 among all the studied models. These findings highlighted the importance to consider the polymorphism of the DNA G4. Interestingly, this correlation resulted always improved with respect to that of the single folds, with the exception of the parallel structure, thus suggesting a key role of this G4 conformation in the interaction network of the tested binders. Moreover, we identified the moieties of the phenanthroline scaffold directly involved in the complex formation. This allowed to rationalize the improved binding affinity always associated with a bis-phenanthroline system and to explain why a phenanthroline substituted with a pyridine ring is favored with respect to the pyrimidine one.
Pranita P. Kore, Madhavi M. Mutha, , Rajesh J. Oswal, Sandip S. Kshirsagar
Open Journal of Medicinal Chemistry, Volume 02, pp 139-148;

Strategies for CADD vary depending on the extent of structural and other information available regarding the target (enzyme/receptor) and the ligands. Computer-aided drug design (CADD) is an exciting and diverse discipline where various aspects of applied and basic research merge and stimulate each other. In the early stage of a drug discovery process, researchers may be faced with little or no structure activity relationship (SAR) information. The process by which a new drug is brought to market stage is referred to by a number of names most commonly as the development chain or “pipeline” and consists of a number of distinct stages. To design a rational drug, we must firstly find out which proteins can be the drug targets in pathogenesis. In present review we reported a brief history of CADD, DNA as target, receptor theory, structure optimization, structure-based drug design, virtual high-throughput screening (vHTS), graph machines.
, Hector Carreno Gutierrez, Rosario Arévalo Arévalo, Nadia S. Chiaramoni,
Open Journal of Medicinal Chemistry, Volume 02, pp 129-138;

Brain developmental disorders in humans, including Autism Spectrum Disorders (ASD) and Down’s syndrome, have been linked to increased serotonin levels. This work was designed to study changes in serotonin levels in the early stages of development with two classes of antipsychotic drugs: Risperidone, a drug that blocks serotonin and dopamine receptors, and fluoxetine, a serotonin reuptake inhibitor. The use of antipsychotic drugs is a solid choice to study the decrease and increase of these neurotransmitters and their influence on development. The study of these parameters will give an idea of the effects of serotonin in early developmental stages. To this end, we examined the effects of risperidone and fluoxetine on the locomotor activity, heart rate and brain development of zebrafish larvae. Our results showed that in larvae exposed to fluoxetine alone, swimming was significantly increased at 9 dpf (days post-fertilization). Erratic and abnormal movements were observed suggesting a toxic effect of fluoxetine. No erratic swimming was observed in larvae treated with fluoxetine plus risperidone. Both drugs presented morphological changes in dopaminergic neurons and mononeurons. Exposure to fluoxetine plus risperidone indicated possible reversal effects. Studies in zebrafish allow obtaining new insights into the side effects of these drugs as well as into the brain control of locomotor activity. Testing several drug-induced changes in behavior and serotonin levels is one of the experimental approaches for screening a new therapeutically relevant compound, and thus, merits further research.
Seun F. Akomolafe, Ganiyu Oboh, Afolabi A. Akindahunsi, Ayodele J. Akinyemi, Olusola Adeyanju
Open Journal of Medicinal Chemistry, Volume 02, pp 119-128;

Oxidative stress has been identified as one of the factors that affects fertility status. Therefore, this study sought to investigate the inhibitory effect of aqueous extract of Moringa oleifera and Newbuoldia laevis leaves on FeSO4 and Sodium Nitroprusside (SNP) induced lipid peroxidation in rat testes in vitro. Incubation of the testes tissue homogenate in the presence of FeSO4 and SNP caused a significant increase in the malondialdehyde (MDA) contents of the testes. The aqueous extract from both Moringa oleifera and Newbuoldia laevis leaves caused a significant decrease in the MDA contents of the testes in a dose-dependent manner. However, aqueous extract from Moringa oleifera leaf (EC50 = 0.29 mg/ml) had a significant (P 0.05) higher inhibitory effect on Fe2+ induced lipid peroxidation in the rat testes homogenate than that of Newbuoldia laevis leaf extract (EC50 = 0.58 mg/ml); while there was no significant (P 0.05) difference between the plant extracts on SNP induced lipid peroxidation in the rat testes homogenates. Therefore, part of the mechanisms through which the water extractable phytochemicals in the leaves protect the testes from oxidative stress may be through their antioxidant activity; DPPH scavenging ability, Fe2+ chelating and reducing power. Therefore, these plants have potential to prevent oxidative stress in testes and improve fertility outcomes.
Joyce Cristina de Oliveira, Carla Renata Kitanish Antonietto, Angélica Cristina Scalabrini, Talita Sanches Marinho, , José Wilson N. Corrêa, Carolina Baraldi Araujo Restini
Open Journal of Medicinal Chemistry, Volume 02, pp 61-71;

Shinya Nakamura, Kazunori Takahira, , , Isao Nakanishi
Open Journal of Medicinal Chemistry, Volume 02, pp 50-60;

Maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) belong to human intestinal alpha-glucosidase and their N-terminal side catalytic domains are called NtMGAM and NtSI, and their C-terminal side catalytic domains are called CtMGAM and CtSI. As an antidiabetic, alpha-glucosidase inhibitor is required to bind to all of these domains to inhibit disaccharides hydrolysis. Salacinol and kotalanol isolated from Salacia reticulata are novel seed compounds for al-pha-glucosidase inhibitor. Even though the complex structures of NtMGAM or NtSI have been determined experimen-tally, those of CtMGAM and CtSI have not been revealed. Thus, homology modeling for CtMGAM and CtSI has been performed to predict the binding mode of salacinol and its derivatives for each domain. The binding affinities for these compounds were also calculated to explain the experimental structure-activity relationships (SARs). After a docking study of the derivatives to each catalytic domain, the MM/PBSA method has been applied to predict the binding affinities. The predicted binding affinities were almost consistent with the experimental SARs. The comparison of the complex structures and binding affinities provided insights for designing novel compounds, which inhibit all catalytic domains.
Adeayo O. Ajala,
Open Journal of Medicinal Chemistry, Volume 02, pp 43-49;

Topomer CoMFA models have been used to optimize the potency of 15 biologically active acridone derivatives se- lected from the literature. Their 3D chemical structures were sliced into three acyclic R groups, to produce a fragment that is present in each training set. The analysis was successful with 3 as the number of components that provided the highest q2 results: q2 is 0.56, which is the cross-validated coefficient for the specified number of components, giving rise to 0.37 standard error of estimate (q2 stderr), and a conventional coefficient (r2) of 0.82, whose standard error of estimate is 0.24. These results provide structure-activity relationship (sar) among the compounds. The result of the To-pomer CoMFA studies was used to design novel derivatives for future studies.
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