Medicinal Chemistry

Generating a 3D structure model of Histamine-4 receptor for Antiinflammatory Drug Design

by Jutti Levita

Conformationally restricted tetrahydro-1-benzoxepin analogs of hallucinogenic phenethylamines

by Nicholas Cozzi

Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-(methylenedioxy)amphetamine

by Nicholas Cozzi

Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines as serotonin-selective reuptake inhibitors with a potentially improved adverse reaction profile

by Nicholas Cozzi

Stereospecific inhibition of monoamine uptake transporters by meta-hydroxyephedrine isomers

by Nicholas Cozzi

Analyzing the Interaction of Andrographolide and Neoandrographolide, Diterpenoid Compounds From Andrographis Paniculata (Burm. F) Nees, to …

by Jutti Levita

Andrographolide Inhibits COX-2 Expression in Human Fibroblast Cells Due to its Interaction with Arginine and Histidine in Cyclooxygenase Site

by Jutti Levita

Andrographolide: A Review of its Anti-inflammatory Activity via Inhibition of NF-kappaB Activation from Computational Chemistry Aspects

by Jutti Levita

Radioiodinasi andrografolid dan biodistribusinya dalam mencit untuk perunut inflamasi

by Jutti Levita

Analyzing the Interaction of Shellegueain A: A Bioactive Compound of Pakis Tangkur (Selliguea feei or Polypodium feei) to Cyclooxygenase Enzyme by Molecular Docking

by Jutti Levita

The inhibition of andrographolide (Andrographis paniculata) on the expression of carbonic anhydrase in LPS-induced human leucocyte cells

by Jutti Levita

Molecular Structure and Antimicrobial Activity of a Luminescent Dinuclear Silver(I) Complex of Phenyl-bis(2-pyridyl)phosphine

by Cina Foroutan-Nejad

Ali Nemati Kharat, Abolghasem Bakhoda, Sahar Foroutannejad, Cina Foroutan-Nejad, ZAAC, 2011, 637, 2260

Phenyl bis(2-pyridyl)phosphine [PhP(2-py)2] and its silver
nitrate complex of formula [Ag2(μ-(PhP(2-py)2)2(NO3)2]... more Phenyl bis(2-pyridyl)phosphine [PhP(2-py)2] and its silver
nitrate complex of formula [Ag2(μ-(PhP(2-py)2)2(NO3)2] (1) were synthesized
and characterized by elemental analysis, IR spectroscopy, single-
crystal X-ray diffraction, and computational studies. The silver(I)
complex 1 with a 1:1 metal-ligand molar ratio is dinuclear cluster with silver atoms in same environments. Biological studies, carried out in
vitro against wide range of gram positive and gram negative bacteria,
have shown that the free [PhP(2-py)2] ligand and its silver complex
show distinct differences in the biological properties.

Interpenetrating polymeric network hydrogel for stomach-specific drug delivery of clarithromycin: Preparation and evaluation

by Ram C Dhakar

Dhakar Ramchand1, Gupta Anish Kumar, Siddiqui Abdul Wadood, Maurya Sheo Datta1,

The aim of this study was to develop a controlled release system targeting antibiotic delivery to the stomach. Themore The aim of this study was to develop a controlled release system targeting antibiotic delivery to the stomach. The
hydrogels were synthesized by using chitosan, poly (acrylic acid) and poly (vinyl pyrrolidone) polymers crosslinked
with glutaraldehyde and N,N’-methylenebisacrylamide. Interpenetrating polymeric network (IPN) hydrogels were prepared
by varying the concentration of crosslinking agent (glutaraldehyde). The amount of chitosan, poly (acrylic acid), poly
(vinyl pyrrolidone) and N,N’-methylenebisacrylamide were kept constant in all formulations. The effect of glutaraldehyde
concentration on the swelling and release characteristics were evaluated. Modalities used to assess the most optimal hydrogel
formulation included high liquid chromatography, FTIR analysis, differential scanning calorimetry, swelling studies, in vitro
drug release study, mucoadhesive study and scanning electron microscopy. The result showed that IPN hydrogels were
greater in swelling, more mucoadhesive and released more drug at lower pH values. Thus, it is believed that the antibiotic
concentration in the stomach might be sustained through this formulation.

HIV-1 RT inhibitors with a novel mechanism of action: NNRTIs that are competing with the nucleotide substrate

by Marco Radi

HIV-1 reverse transcriptase (RT) inhibitors currently used in antiretroviral therapy can be divided into two classes:... more HIV-1 reverse transcriptase (RT) inhibitors currently used in antiretroviral therapy can be divided into two classes: (i) nucleoside analog RT inhibitors (NRTIs), which compete with natural nucleoside substrates and act as terminators of proviral DNA synthesis, and (ii) non-nucleoside RT inhibitors (NNRTIs), which bind to a hydrophobic pocket close to the RT active site. In spite of the efficiency of NRTIs and NNRTIs, the rapid emergence of multidrug-resistant mutations requires the development of new RT inhibitors with an alternative mechanism of action. Recently, several studies reported the discovery of novel non-nucleoside inhibitors with a distinct mechanism of action. Unlike classical NNRTIs, they compete with the nucleotide substrate, thus forming a new class of RT inhibitors: nucleotide-competing RT inhibitors (NcRTIs). In this review, we discuss current progress in the understanding of the peculiar behavior of these compounds.

Design and Synthesis of Thiadiazoles and Thiazoles Targeting the Bcr-Abl T315I Mutant: from Docking False Positives to ATP-Noncompetitive Inhibitors

by Marco Radi

In an effort to optimize our previously identified dual Src/Abl hits, a new series of 1,3,4-thiadiazoles and... more In an effort to optimize our previously identified dual Src/Abl hits, a new series of 1,3,4-thiadiazoles and 1,3-thiazoles were designed and synthesized, paying particular attention to the reduction of their lipophilicity and to the improvement of the affinity towards the drug-resistant T315I mutant. Compound 5 was identified as a promising allosteric inhibitor of the T315I mutant.

Identification and characterization of novel c-Abl / c-Src dual kinase inhibitors which are active against a large panel of tumour progenitor cells that express stem cell marker

by Marco Radi

Background

The non-receptor tyrosine kinases c-Abl and c-Src are overexpressed in various solid human... more Background

The non-receptor tyrosine kinases c-Abl and c-Src are overexpressed in various solid human tumours. Inhibition of their hyperactivity represents a molecular rationale in the combat of cancerous diseases. Here we examined the effects of a new family of pyrazolo [3,4-d] pyrimidines on a panel of 11 different murine lung tumour progenitor cell lines, that express stem cell markers, as well as on the human lung adenocarcinoma cell line A549, the human hepatoma cell line HepG2 and the human colon cancer cell line CaCo2 to obtain insight into the mode of action of these experimental drugs.

Methodology/Principal Findings

Treatment with the dual kinase inhibitors blocked c-Abl and c-Src kinase activity efficiently in the nanomolar range, induced apoptosis, reduced cell viability and caused cell cycle arrest predominantly at G0/G1 phase while western blot analysis confirmed repressed protein expression of c-Abl and c-Src as well as the interacting partners p38 mitogen activated protein kinase, heterogenous ribonucleoprotein K, cyclin dependent kinase 1 and further proteins that are crucial for tumour progression. Importantly, a significant repression of the epidermal growth factor receptor was observed while whole genome gene expression analysis evidenced regulation of many cell cycle regulated genes as well integrin and focal adhesion kinase (FAK) signalling to impact cytoskeleton dynamics, migration, invasion and metastasis.

Conclusions/Significance

Our experiments and recently published in vivo engraftment studies with various tumour cell lines revealed the dual kinase inhibitors to be efficient in their antitumour activity.

New insight into small molecules inhibitors of Bcr-Abl

by Marco Radi

Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the... more Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the Bcr-Abl fusion gene on the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase (TK) Bcr-Abl. This enzyme leads to the malignant transformation of primitive hematopoietic cells and to the consequent disease. The central role of Bcr-Abl in the pathogenesis of CML culminated in the discovery of imatinib (an ATP-competitive inhibitor), which is currently the frontline therapy for CML. Unfortunately, the initial enthusiasm generated by its high response rate has been dampened by the development of resistance, especially in the advanced phases of CML. To overcome imatinib resistance, several second-generation ATP-competitive inhibitors endowed with increased potency against imatinib-resistant mutants have been developed: the dual Src/Abl inhibitor dasatinib and the Abl inhibitor nilotinib have been recently approved by US-FDA for the treatment of imatinib-resistant CML, and many other compounds are currently in clinical trial. Although second-generation TK inhibitors have shown to be clinically effective against most of the imatinib-resistant mutants, to date poor results have been obtained in the treatment of the Bcr-Abl T315I mutant. In this review we will report the most interesting second-generation Abl and dual Src/Abl inhibitors recently entered in clinical trial, but also the new ATP-competitive and uncompetitive inhibitors published in the last few years, focusing on their chemical structure, mechanism of action, and structure-activity relationship.

Targeting the human DEAD-box polypeptide 3 (DDX3) RNA helicase as a novel strategy to inhibit viral replication

by Marco Radi

Compounds currently used for the treatment of HIV-1 Infections are targeted to viral proteins. However, the high... more Compounds currently used for the treatment of HIV-1 Infections are targeted to viral proteins. However, the high intrinsic mutation and replication rates of HIV-1 often lead to the emergence of drug resistant strains and consequent therapeutic failure. On this basis, cellular cofactors represent attractive new targets for HIV-1 chemotherapy, since targeting a cellular factor that is required for viral replication should help to overcome the problem of viral resistance. We and others have recently reported the identification of compounds suppressing HIV-1 replication by targeting the cellular DEAD-box helicase DDX3. These results provide a proof-of-principle for the feasibility of blocking HIV-1 infection by rendering the host cell environment less favorable for the virus. The rationale for such an approach and its implications in potentially overcoming the problem of drug resistance related to drugs targeting viral proteins will be discussed in the context of the known cellular functions of the DEAD-box helicase DDX3.

ATP-competitive inhibitors of mTOR: an update

by Marco Radi

mTOR (mammalian target of rapamycin) is a serine-threonine kinase belonging to the PI3K/Akt/mTOR signalling pathway... more mTOR (mammalian target of rapamycin) is a serine-threonine kinase belonging to the PI3K/Akt/mTOR signalling pathway that is involved in several cell functions, including growth, proliferation, apoptosis and autophagy. mTOR hyperactivation has been detected in several human cancers, thus representing, together with its upstream effectors, an important target for cancer therapy. mTOR exists in two different complexes in cells, mTORC1 and mTORC2 which could both be targeted by potential anticancer agents. Rapamycin, the selective and allosteric inhibitor of mTOR, inhibits the enzyme in mTORC1, but not in mTORC2. In the last few years a number of mTOR ATP-competitive inhibitors has been reported acting on mTOR in both complexes and possessing a more complete anticancer activity in comparison with that of rapamycin and its derivatives. mTOR shares high sequence homology in the hinge-region with PI3K that is a lipid kinase upstream to mTOR in the same signaling pathway; for this reason some compounds originally developed as PI3K inhibitors later showed to also target mTOR. As indicated by preclinical and clinical studies, compounds acting on more than one target could result in a better biological response and in enhanced therapeutic potential and also dual PI3K/mTOR inhibitors result of great interest as potential antitumor agents. This review mainly reports the recently discovered mTOR ATP-competitive inhibitors in terms of medicinal chemistry, classified by their chemical structures, focusing on SAR and modelling studies that led to the discovery of very potent and selective agents, such as AZD-8055, OSI-027 and INK128, already entered clinical trials, or WYE-132, Torin1 and others in preclinical studies. Also some examples of dual PI3K/mTOR inhibitors, including PI-103, GNE477, WJD008 and GSK2126458 are reported together with their biological and clinical data.

Inhibition of purple acid phosphatase with α-alkoxynaphthylmethylphosphonic acids

by Jeffrey Y. W. Mak

McGeary, R. P.; Vella, P.; Mak, J. Y. W.; Guddat, L. W.; Schenk, G. Bioorg. Med. Chem. Lett. 2009, 19, 163.

Purple acid phosphatases (PAPs) are binuclear hydrolases that catalyse the hydrolysis of a range of phosphorylated... more Purple acid phosphatases (PAPs) are binuclear hydrolases that catalyse the hydrolysis of a range of phosphorylated substrates. Human PAP is a major histochemical marker for the diagnosis of osteoporosis. In patients suffering from this disorder, PAP activity contributes to increased bone resorption and, therefore, human PAP is a key target for the development of anti-osteoporotic drugs. This manuscript describes the design and synthesis of derivatives of 1-naphthylmethylphosphonic acids as inhibitors of PAP. The Ki values of these compounds are as low as 4 μM, the lowest reported to date for a PAP inhibitor.