Mini Reviews in Medicinal Chemistry

Published by Bentham Science Publishers
Online ISSN: 1389-5575
Publications
Article
Imidazo[1,2-a]pyridine is a bicyclic system with a bridgehead nitrogen atom, of growing interest in medicinal chemistry. The paper deals with the recent progress realised in the comprehension of the pharmacological properties of this scaffold. From the many imidazo[1,2-a]pyridine analogues described in the literature, those discussed herein will be presented in three parts concerning first the enzyme inhibitors, then the receptor ligands and finally the anti-infectious agents.
 
Article
The excitatory neurotransmitter glutamate interacts with ionotropic and metabotropic receptors that mediate a variety of normal signalling processes in the brain. However, excessive stimulation of these receptors appears to be involved in neurodegenerative processes, at least in animal models. Ionotropic glutamate receptors can be divided into NMDA and non-NMDA (AMPA and KA) subtypes on the basis of t heir preferential affinities for the synthetic excitatory amino acids N-methyl-D-aspartic acid (NMDA) or 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA), respectively. Although most of the early evidence favoured a role for NMDA receptors in the excitotoxic processes, it has been recognised that AMPA receptors may also be significantly involved in neuronal death. As a consequence, the synthesis of specific AMPA antagonists has raised much interest as source of potential drugs for epilepsy and acute and chronic neurodegenerative diseases. The discovery of RPR117824, a potent and selective AMPA receptors antagonist endowed with anticonvulsant and neuroprotective properties, induced growing interest on dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazine series. This review covers the main chemical course leading to the most promising compounds as well as the pharmacological properties of this original class of AMPA receptor antagonists.
 
Article
1-Monosubstituted 1,2,3-triazoles have widespread applications in diverse fields, and their preparation has attracted increasing attention. This review mainly covers the modern advances in the synthesis of these heterocycles based on different methods including the substitution of 1H-1,2,3-triazole and cycloaddition reactions involving moieties, such as acetylene, substituted acetylene, and vinyl compounds, among others.
 
Article
1,2,3-Triazine is an interesting class of heterocyclic compounds. Various synthetic analogs of 1,2,3-triazine have been prepared and evaluated for many pharmacological activities in different models with desired findings. Some analogs have shown potent pharmacological activity and may be considered as lead molecule for the development of future drugs. This review is an attempt to organize the chemical and pharmacological aspects of 1,2,3-triazine analogs reported till date systematically since 1963.
 
Contd…. 
Article
1,2,4-Triazine nucleus is a prominent structural core system present in numerous pharmacologically active compounds. Till date, various 1,2,4-triazine analogs, possesing a wide range of potent pharmacological activities, have been reported. This review is an attempt to compile the medicinal chemistry aspects of various synthesized 1,2,4-triazine analogs reported so far. Keywords: Anticancer activity, anticonvulsant activity, antimicrobial activity, 1,2,4-triazine.
 
Article
1,2,4-Thiadiazole is a distinctive class of small heterocyclic thiol trapping agents that serve as an interesting pharmacophore in the design of inhibitors targeting the cysteine residues of proteins. X-Ray crystal structures of enzyme-inhibitor complex indicate that the cysteine thiol reacts with the N-S bond of the thiadiazole moiety to form a disulfide bond resulting in the inactivation of the enzymes. This review addresses the medicinal chemistry and various properties of 1,2,4-thiadiazoles in their potential as new electrophilic "warheads" for targeting the cysteine residues of biomolecules (e.g, H+/K+ ATPase), and cysteine-dependent enzymes (e.g., cathepsin B and transglutaminase).
 
Article
In this short review the methods of preparation of novel 1,2,4,5-tetraoxacycloalkanes and the related peroxides are summarized, with the emphasis on the usefulness of 1,1-bishydroperoxides as the precursor. Also, their antimalarial activities in vitro and in vivo are discussed.
 
Article
Methods for formation of 1,2,4,5-tetraoxanes are summarized and antimalarial activities of 1,2,4,5-tetraoxanes are discussed.
 
Article
Beta-(1,3)-glucans are widely distributed within microorganisms or seaweeds in which they act as membrane components or for energy storage, respectively. Since these glucans are not biosynthesized by mammals, they are likely to activate the immune system of their host. Since the discovery of their positive involvement as immunomodulator agents, numerous studies were published all around the glycosciences. These works deal with purification procedures, analytical chemistry, synthetic processes, chemical modification of the natural polysaccharides, determination of their physicochemical properties, and assessment of their biological and medicinal effects through in vitro and in vivo studies. This article aims at presenting some recent results linked to beta-(1,3)-glucans through two closely connected points of view, i.e. biology and chemistry. Biological aspects will be focused more particularly on discovery of some receptors present on immunocompetent cells and scope and limitations of chemical synthesis and/or modifications will be described. Moreover, this paper will also introduce some new chemo-enzymatic synthetic methods using wild-type or mutant glycosidases and will be extended to novel opportunities of applications of beta-(1,3)-glucans in nanotechnology resulting from a better understanding of their self-assembling propensity in aqueous media.
 
Article
The chemistry of 1,3,4-thiadiazoles is very well known. The cyclization of suitable open- chain organic molecules is a classical and common approach to the synthesis of various 2,5-disubstituted 1,3,4-thiadiazoles. They are widely known as compounds with various kinds of biological activities showing anticancer properties against human cancers and acting as diuretic, antibacterial, antifungal, antitubercular and leishmanicidal agents. Many of them influence on OUN exhibiting anticonvulsant, anti-inflammatory, antidepressant, analgesic and anxiolytic effects. The molecular target of 1,3,4-thiadiazoles includes the following enzymes: carbonic anhydrase (CA), cyclooxygenase (CO), neutral endopeptidase (NEP), aminopeptidase N (APN), matrix metalloproteinases (MMPs), phosphodiesterases (PDEs) and c-Src/Abl tyrosine kinase. In this presentation, recent achievements in the medicinal chemistry of 1,3,4-thiadiazole based compounds are reviewed.
 
Article
There has been considerable interest in the development of novel compounds with anticonvulsant, antidepressant, analgesic, anti-inflammatory, antiallergic, antipsychotic, antimicrobial, antimycobecterial, antitumour, antiviral and antitubercular activities. 1,3,4-oxadiazoles constitute an important class of compounds for new drug development. Therefore, many researchers have synthesized these compounds as target structures and evaluated their biological activities. These observations led to the development of new 1,3,4-oxadiazole derivatives. This review article describes the various biological activities associated with 1,3,4-oxadiazole ring system and is useful in guiding the researchers across the world working on this moiety and consequently have been instrumental in the advancement of 1,3,4-oxadiazole chemistry.
 
Contd….. 
Article
1,3,4-oxadiazole, a privileged structure, endows its derivatives with broad and potent biological functions, especially in antiviral activities, including anti-HIV, anti-HCV, anti-HBV, anti-HSV activities, etc. Molecular modeling and pharmacokinetic studies have demonstrated that the introduction of 1,3,4-oxadiazole ring to the inhibitors can change their polarity, flexibility as well as metabolic stability, and 1,3,4-oxadiazole scaffold can also act as acceptors of hydrogen bonds formation, which make it possible to be used as a isosteric substituent for amide or ester groups. This review focuses on the recent advances in the synthesis of 1,3,4-oxadiazole ring and mainly the discovery, biological activities investigations and structural modifications of several distinct classes of 1,3,4-oxadiazoles as potent antiviral agents. In addition, the binding models of some representative 1,3,4-oxadiazoles were also discussed, which provide rational explanation for their interesting antiviral activities, and also pave the way for further optimization of 1,3,4- oxadiazole based antiviral agents.
 
Antiepileptic Activity of the Synthesized Compounds. 
Results of Molecular Docking Study of Target Compounds.
Summary of Physical Characteristics Compounds and their Reaction Times (3a-3e).
Article
Epilepsy is one of the commonly occurred chronic neurological disorders which involve abnormal electrical impulses in the brain. It is also characterized by the sudden loss of consciousness, followed by abnormal shaking of the body. Though there are various types of antiepileptic drugs available clinically, but the treatment of epilepsy remains still inadequate because of their toxicity and idiosyncratic side effects. Thus, there is essential requirement to develop safer drug for the treatment of convulsion with lower side effects with improved bioavialabity. Because of the structural similarity of the target compounds with the antiepileptic drug such as Phenytoin and Lamotrigine, it was considered to carry out the docking of target compounds into the active site of the voltage-gated sodium channels. So, a series of 1,3,4-thiadiazole derivatives have been prepared by using an appropriate synthetic methodology. The chemical structures of the synthesized compounds were confirmed by means of IR, 1H NMR, and Mass spectroscopy. The antiepileptic activity of the synthesized compounds was evaluated as per maximal electroshock induced seizures (MES) models in rat at dose of 30, 100 and 300mg/kg respectively. Among the tested compounds, some of them exhibited significant anticonvulsant activity as compared to the standard anticonvulsant drug, Phenytoin in a dose depended manner. The neurotoxicity study was carried out by applying the rotarod test.
 
Article
The synthesis of novel compounds libraries and screening among these is a rapid and effective approach for discovery of potential chemical agents and become important a major objective in pharmaceutical chemistry research. As the typical heterocyclic compounds, 1,3,4-oxadiazole derivatives exhibit broad spectrum of biological activities and are as a vital leading compounds for the development of chemical drugs. Herein, we focus on the synthesis and screening of novel 1,3,4-oxadiazoles derivatives with antimicrobial, antitumor or antiviral activities during the past decade. In this review, we discussed the synthetic development of 1,3,4-oxadiazoles derivatives, and also the relevant bioactivity and their perspective as the potential chemical drugs.
 
Article
Cross-resistance development against most peptidic HIV-1 protease inhibitors (PI) forces the development of nonpeptidic alternatives. The classes of nonpeptidic protease inhibitors was limited so far to cyclic ureas and 4-hydroxy-2-pyrones with problems of limited bioavailability by extensive metabolism and protein binding. Cage dimeric 4-aryl-1,4-dihydropyridines have been developed as third class of nonpeptidic PIs. In the following synthesis, molecular modeling and biological activities of a first series of the novel PIs are reviewed. Bioavailability of the dimers will not be limited by protein binding and metabolism as far as evaluated.
 
Article
The biological activity of many low molecular weight antitumor compounds appear to be related to their mode and specificity of interaction with particular DNA sequences. Such small molecules are of considerable interest in chemistry, biology and medicine. Most of the anticancer drugs employed clinically exert their antitumor effect by inhibiting nucleic acid (DNA or RNA) or protein synthesis. Inhibition can occur for example through cross-linking of bases in DNA or binding to and inactivation of enzymes necessary for the synthetic processes. It is evident that DNA is an important cellular target for many anticancer agents. Much information has been obtained from molecular genetics, i.e. replication of DNA and its transcription to RNA, which provides the template for protein synthesis. DNA is a well-characterized intracellular target but its large size and sequential nature makes it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a wide variety of potential biological responses. In this context PBDs (pyrrolo[2,1-c][1,4]benzodiazepines), a group of potent naturally occurring antitumor antibiotics produced by various Streptomyces species, are one of the most promising types of lead compounds. They differ in the number, type and position of substituent in both their aromatic A-ring and Py C-rings, and in the degree of saturation of the C-rings which can be either fully saturated or unsaturated at either C2-C3 (endocyclic) or C2 (exocyclic). There is either an imine or carbinolamine methyl ether at the N10-C11 position. This latter is an electrophilic center responsible for alkylating DNA. In the search for compounds with better antitumor selectivity and DNA sequence specificity many PBD analogues have been synthesized in an attempt to increase their potency against tumor cells. We review here recent progress on pyrrolo[2,1-c][1,4]benzodiazepine (PBDs) analogues and their conjugates, also the progress and developments of PBD conjugates with polyamides (information reading molecules in the minor groove of DNA). For example, the cross-linking efficiency of PBD dimers is much greater than that of other cross linkers including cisplatin and melphalan. A large number of PBD dimers and polyamide conjugates with varying linker lengths and bearing different heterocycles at different positions in the PBD ring synthesized in our group and their pharmacological properties have been reviewed.
 
Article
The [1,4]-benzodiazepine is an important class of heterocyclic compounds and clinically used for many ailments in humans. The [1,4]-benzodiazepine has unique structure that mimics the peptide linkage. This interesting observation completely shifted the interest of medicinal chemist for [1,4]-benzodiazepine from CNS acting drugs to anticancer agent. During last few decades, large number of reports has appeared in the literature highlighting the anticancer activity of [1,4]-benzodiazepines. Here, in this article, we have discussed the brief synthesis, origin of [1,4]-benzodiazepines as anticancer agent, its mechanism of action and latest developments in this field. We have compiled the most important literature reports from last few decades to till date.
 
Article
1,4-Dihydropyridine (1,4-DHP) derivatives nifedipine of which the prototype, are the most popular drugs having calcium antagonistic activity. Fused 1,4-dihydropyridines (DHPs) have also exhibit calcium modulatory activities. In this article, we emphasize calcium channels and fused 1,4-DHP derivatives affecting calcium channels. In addition, the basic considerations of synthesis, metabolism, structure-activity relationships and the latest developments on fused 1,4-DHP derivatives will be reviewed. This review also has extended examples of fused 1,4-DHP derivatives having cited activities synthesized by our group.
 
Article
1,4-Benzothiazine (1,4-BT) derivatives have been reported to exhibit a wide range of pharmacological properties including antifungal, immunostimulating, anti-aldoso-reductase, anti-rheumatic, anti-allergic, vasorelaxant, anti-arrhythmic, anti-hypertensive, neuroprotective and cytotoxic activities. These different effects indicate that 1,4-BT is a template potentially useful in medicinal chemistry research and therapeutic applications.
 
Properties of Voltage-gated Calcium Channels 
Activities of 1,4-Dihydropyridines at Potassium Channels 
Article
The 1,4-dihydropyridine nifedipine is a prototypical example of the group of calcium channel blockers that also includes a number of second and third generation agents. These drugs enjoy substantial therapeutic prominence for their cardiovascular actions, including hypertension and angina. These actions are exerted at a specific member of the voltage-gated calcium channel family -the L-type channel. However, it is increasingly clear that the 1,4-dihydropyridine structure is a pharmacophoric template or "privileged structure" that, when appropriately substituted, can exert potent and selective actions at a diverse set of membrane receptors, including ion channels, G protein-coupled receptors and enzymes. This review will summarize the actions of 1,4-dihydropyridines at these receptors and advance the case that the 4-phenyl-1,4-dihydropyridine structure is a particularly versatile drug template. Part I of the review will summarize actions at ion channels and part II will summarize actions at other receptor systems.
 
Article
The aim of this review is precisely to give a comprehensive account of the large volume of work carried out on 1,4-diazepines regardless of the degree of unsaturation in the diazepine system. This review mainly emphasizes recent work on the diazepines also including earlier work.
 
Article
CXCR3 and CCR5 are chemokine receptor that are predominantly expressed on the surface of Th1 polarized T cells. In a variety of human and experimental autoimmune diseases the enhanced expression of CXCR3 and CCR5 binding chemokine ligands is followed by the recruitment of CXCR3- and CCR5-positive T cells, indicating an important role for these chemokine receptors in T cell-mediated tissue damage. In this review, we summarize a number of in vivo studies available on the neutralization of CXCR3 and CCR5 in inflammatory disease, and specifically focus on the potential therapeutic effects of CXCR3 and CCR5 blockade in human autoimmune disease and organ transplantation.
 
Article
Polyphenols are a large family of naturally occurring plant products and are widely distributed in plant foods, such as, fruits, vegetables, nuts, flowers, bark and seeds, etc. These polyphenols contribute to the beneficial health effects of dietary products. Clinical and epidemiological studies suggest that exposure of the skin to environmental factors/pollutants, such as solar ultraviolet (UV) radiation induce harmful effects and leads to various skin diseases including the risk of melanoma and non-melanoma skin cancers. The incidence of non-melanoma skin cancer, comprising of squamous cell carcinoma and basal cell carcinoma, is a significant public health concern world-wide. Exposure of the skin to solar UV radiation results in inflammation, oxidative stress, DNA damage, dysregulation of cellular signaling pathways and immunosuppression thereby resulting in skin cancer. The regular intake of natural plant products, especially polyphenols, which are widely present in fruits, vegetables, dry legumes and beverages have gained considerable attention as protective agents against the adverse effects of UV radiation. In this article, we first discussed the impact of polyphenols on human health based on their structure-activity relationship and bioavailability. We then discussed in detail the photoprotective effects of some selected polyphenols on UV-induced skin inflammation, proliferation, immunosuppression, DNA damage and dysregulation of important cellular signaling pathways and their implications in skin cancer management. The selected polyphenols include: green tea polyphenols, pomegranate fruit extract, grape seed proanthocyanidins, resveratrol, silymarin, genistein and delphinidin. The new information on the mechanisms of action of these polyphenols supports their potential use in skin photoprotection and prevention of photocarcinogenesis in humans.
 
Article
Exhaled breath analysis for clinical diagnosis and therapeutic monitoring is described with special reference to the techniques used and the underlying chemistry and physics involved. Brief outlines are given of the research carried out to date, and prospects for the future of this potentially valuable non-invasive technique are indicated.
 
Article
This review paper has attempted information specific to the title compound. This survey of the literature data provides useful information about the design and stabilities of the triorganotin with biologically active ligands. Up to now, considerable efforts have been made to synthesize and characterize triorganotin(IV) schiff base complexes with the general formulae R3ML [R = organic group, M: Sn and L: schiff base] and many studies have been focused in order to understand bioassay results. Users with an interest in this substance are strongly encouraged for future research that this is still a very open field.
 
Article
Glucocorticoid action is linked to the development of obesity and insulin resistance. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been proposed as a strategy to suppress glucocorticoid action in a tissue-specific manner. A large variety of 11beta-HSD1 inhibitor classes are under investigation by the pharmaceutical industry to treat type 2 diabetes and obesity.
 
Article
The 14-position of natural opiates (e.g. morphine) are unsubstituted, however synthetic approaches have uncovered that functionalizing position 14 gives rise to a wide range of diverse activities. This review focuses on SAR of the position, with the aim of aiding in the search for opioid analgesics with improved clinical profiles.
 
Article
The continuing emergence of bacterial resistance has provided an incentive for recent intensified research on macrolide antibiotics. Belonging to the macrolide family, 16-membered macrolides also experience a renewed interest in further exploration. The medicinal potential of 16-membered macrolides in search for new antibacterials stems from some advantages over 14-membered macrolides, such as gastrointestinal tolerability, structural flexibility, and lack of inducible resistance. Thus, compared with abundant articles on various 14-membered macrolide derivatives in the literature, this review will highlight some representative 16-membered macrolide antibiotics and their recently discovered analogs. Furthermore, the action and resistance mechanisms of 16-membered macrolide antibiotics will be elucidated as well to assist the drug design.
 
Article
Recently a few new purine nucleoside analogues (PNA) have been synthesized and introduced into preclinical and clinical trials. The transition-state theory has led to the design of 9-deazanucleotide analogues that are purine nucleoside phosphorylase (PNP) inhibitors, termed immucillins. Among them the most promising results have been obtained with forodesine. Forodesine (BCX-1777, Immucillin H, 1-(9-deazahypoxanthin)-1,4-dideoxy-1,4-imino-D-ribitol) has carbon-carbon linkage between a cyclic amine moiety that replaces ribose and 9-deaza-hypixanthine. The drug is a novel T-cell selective immunosuppressive agent which in the presence of 2'-deoxyguanosine (dGuo) inhibits human lymphocyte proliferation activated by various agents such as interleukin-2 (IL-2), mixed lymphocyte reaction and phytohemagglutinin. In the mechanism of forodesine action two enzymes are involved: PNP and deoxycytidine kinase (dCK). PNP catalyzes the phosphorolysis of dGuo to guanine (Gu) and 2'-deoxyribose-1-phosphate, whereas dCK converts dGuo to deoxyguanosino-5'-monophosphate (dGMP) and finally to deoxyguanosino-5'-triphosphate (dGTP). The affinity of dGuo is higher for PNP than for dCK. Nevertheless, if PNP is blocked by forodesine, plasma dGuo is not cleaved to Gu, but instead it is intracellularly converted to dGTP by high dCK activity, which leads to inhibition of ribonucleotide reductase (RR), an enzyme required for DNA synthesis and cell replication, which eventually results in apoptosis. Forodesine is active in some experimental tumors in mice, however it could be used for the treatment of human T-cell proliferative disorders and it is undergoing phase II clinical trials for the treatment of T-cell non-Hodgkin's lymphoma, which includes cutaneous T-cell lymphoma (CTCL). Moreover, recent preclinical and clinical data showed activity of forodesine in B-cell acute lympholastic leukemia (ALL).
 
Article
The favourable nuclear properties of copper-67 and rhenium-188 for therapeutic application are described, together with methods for the chemical synthesis of a number of derivatives. Survival from invasive bladder cancer has changed little over the past 20 years. The intravesicular administration of Cu-67 or Re-188 radiopharmaceuticals in the treatment of bladder cancer offers some promise for improvement in this situation.
 
Article
Attempts have been made to find specific antigens for a novel NKT cell subset bearing invariant V alpha 19-J alpha 33 TCR alpha chains (V alpha 19 NKT cell). Comprehensive examinations revealed substantial antigenic activity in synthetic alpha-mannosylceramide (ManCer) that was presented by MR1. Structural modification of the sphingosine moiety of alpha-ManCer improved antigenic activity to enhance either Th1 or Th2 -promoting cytokine production by V alpha 19 NKT cells. Such alpha-ManCer analogues will be useful for developing new therapies as immunomodulators.
 
The inhibition of HIF-1 expression after miRNA transfection. A, Western blotting analysis of HIF-1 expression; B, Inhibition effect of HIF-1 expression by miRNA at different time.
Article
Hypoxia-inducible factor (HIF)-1α is over-expressed in hepatocellular carcinoma (HCC) and degraded by ubiquitin-proteasome pathways under normoxic conditions. Hepatocyte hypoxia enhances proliferation, angiogenesis, metastasis, chemoresistance, and radioresistance of HCC. The importance role of HIF-1α expression in HCC may improve the prognostic and therapeutic technique. This article reviews the HIF-1α expression and its gene during the rat HCC development, the level of HIF-1α expression in HCC patients, and the effect of silencing HIF-1α gene by miRNA on inhibition of HepG2 cell proliferation.
 
Article
Leishmaniasis affects more than 12 million people in 98 countries, the infection being caused by more than 20 species of protozoan parasites belonging to the genus Leishmania and spread by sandflies bite. Poor sanitary conditions, malnutrition, deforestation and urbanization increase the risk for leishmaniasis. Leishmaniasis is the only tropical disease treated with non-anti-leishmanial drugs, among which liposomal amphotericin B, a combination of pentavalent antimonials and paromomycin and miltefosine, that are highly toxic, represent the most used ones. Drug resistance is now widespread and the search for new molecular targets is open. Topoisomerase 1B, that controls the topological state of DNA and is essential for the parasites viability, has been detected as a promising target for antileishmaniasis therapy. The enzyme presents structural/functional differences with the human counterpart, making it unique among Eukarya. Here we review the structural features of this enzyme and the drugs that can be developed and used for this specific targeting.
 
(a). Represents the Loops Surrounding the Active Site (PTP1B Numbering is Followed). 
Article
Even though protein tyrosine phosphatase has been identified as a validated therapeutic target over a decade for type II diabetes and obesity, developing a selective inhibitor to protein tyrosine phosphatase 1B (PTP1B) over other cellular PTPases has been a complicated task owing to the highly conserved and polar nature of the PTP1B catalytic site. Virtual screening study of in-house chemical depository resulted in the prioritization of few low molecular weight compounds as PTP1B inhibitors. The in-vitro pNPP assays were carried out on prioritized compounds in both PTP1B and T-cell protein tyrosine phosphatase (TCPTP). From this we identified four low molecular weight compounds as PTP1B inhibitors, of which the compound AU-2439 has shown 5 fold selectivity towards PTP1B over highly homologous TCPTP. In this short communication selectivity of AU-2439 is explained based on interaction with critical active site residues in both proteins using docking models.
 
Inhibition of dimorphic transition in C. albicans ATCC 10231, treated with A: compound 1 and B: compound 3. Results are expressed as mean (±SD) of three independent assays ***P<0.001.
Article
The antimicrobial activity of sixteen new N-heteroarylated 1H-(benz)imidazoles was evaluated against clinically relevant bacteria (Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa) and fungi (Candida, Aspergillus and dermatophyte) species according to the Clinical and Laboratory Standards Institute guidelines. None of the tested compounds were active against Gram negative bacteria, but only against S. aureus, that was particularly susceptible to N-thianthrenyl- and N-dibenzothienyl imidazole derivatives. Most of the imidazole derivatives showed a broad spectrum of antifungal activity in all tested fungal strains, including fluconazole-resistant species, with a particularly low minimum inhibitory concentration (MIC) for dermatophytes. N-(dibenzofuran-4-yl)-1H-imidazole (1) and N-(dibenzothien-4-yl)-1H-imidazole (3) showed the highest antifungal potential, being most active against C. albicans. Some N-heteroarylated benzimidazoles showed low activity for fungi with the exception of 3-(1H-benzo[d]imidazol-1-yl)quinoline (14) which was selective against dermatophytes (MIC=4-16 µg/mL). The effect of the active compounds in the inhibition of the dimorphic transition, ergosterol biosynthesis and mitochondrial activity was evaluated in Candida albicans. Compounds 1 and 3 showed the capacity to inhibit the germ tube formation in C. albicans, reduced the ergosterol production and impaired the mitochondrial function. Compounds 1 and 3 showed antimicrobial activity and low cytotoxicity, being of interest for further investigation concerning specially the development of new antifungal agents.
 
Article
2-Phenyl-3-hydroxy-4(1H)-quinolinones can be considered as aza-analogues of flavones, compounds which are known for the wide-range of their biological activity. These quinolinones were studied as inhibitors of topoisomerase, gyrase and IMPDH. They were tested for anticancer activity in-vitro and were also shown to possess immunosuppressive properties. This review is the first summarizing the synthesis and activity of the mentioned quinolinones.
 
Article
Advancements in understanding of the genetics, genomics, biochemistry and the pharmacology of cancer in human, have driven the current cancer chemotherapy to intently focus on development of target-based approaches rather than conventional approaches. From among the various targets identified, validated and inhibited at different hallmarks of cancer, protein tyrosine kinases (PTKs) have been exploited the most. Insulin receptors (IRs), insulin like growth factor receptors (IGF-1R) and their hybrid receptors belong to tyrosine kinase receptor (TKR) family, constitute a structural homology among them and generate a growth promoting IGF system on binding with either insulin, IGF-1 or IGF-2. The system induces the mitogenic effects through a torrent of cell signals produced as a result of cross talk with other growth promoting peptides and steroidal hormones, ultimately resulting in hijacking apoptosis and increasing cell proliferation and cell survival in cancer cells. Various strategies such as anti-IGF-1R antibodies, IGF-1 mimetic peptides, antisense strategies, IGF-1R specific peptide aptamers, targeted degradation of IGF-1R and expression of dominant negative IGF-1R mutants have been explored to inhibit the IGF-1R signaling. However, targeting IGF-1R with small molecules has gained considerable attention in last few years due to their ease of synthesis, ease of optimization of absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters, oral route of administration, lesser side effects and cost effectiveness. The present review provides a broad overview and discusses the highlights on discoveries, SAR studies and binding interactions of small molecules with either IGF-1R active or allosteric sites reported till date.
 
Article
Discovery of novel drugs that are able to prevent angiogenesis is a fast growing branch of cancer research. Current approaches to cancer chemotherapy include the use of alkylating agents, antimetabolites, antitumor antibiotics, platinum analogs and drugs derived from natural compounds. However, most of the currently used chemotherapeutic drugs have adverse side effects on normal healthy cells. In addition to the classical targets of cancer chemotherapy, prevention of angiogenesis through the regulation of indigenous angiogenic factors is a leading approach of developing selective novel anticancer drugs. Because of their low toxicity, there is increasing interest in exploring specific dietary phytochemicals as possible antiangiogenic agents. In this mini-review, selected flavonoids (e.g., apigenin, luteolin, quercetin and epigallocatechin-3-gallate, which are a group of plant polyphenols) that are able to regulate angiogenesis in in vitro and in vivo systems are discussed in light of their potential to be exploited as novel anticancer drugs.
 
Article
6H-Indolo[2,3-b]quinoxaline is a planar fused heterocyclic compound exhibited wide variety of pharmacological activities mainly develop through DNA intercalation. The thermal stability of the intercalated complex (DNA and 6H-indolo[2,3-b]quinoxaline derivatives) is important for the elucidation of anticancer, antiviral and other activities. This thermal stability depends on the type of substituents and side chains attached to the 6H-indolo[2,3-b]quinoxaline nucleus and also the orientation of the side chain towards the GC rich minor groove of the DNA. The highly active derivatives such as NCA0424, B-220 and 9-OH-B-220 have brought its multiple activities by higher thermal stability of the intercalation complex. Interestingly, these compounds possessed poor inhibitory activity on topoisomerase II enzyme, but have significant MDR modulating activities. This review concluded that this pharmacophore can be used for the development of novel molecules with different activities.
 
Article
Raxofelast, also named IRFI 016 or (+/-)5-(acetyloxy)-2,3-dihydro-4,6,7-trimethyl-2-benzofuranacetic acid, belongs to a family of novel molecules designed with the aim to maximize antioxidant potency of phenols related to Vitamin E (alpha-tocopherol). This review will focus on the antioxidant and radical scavenging activity of this new promising compound.
 
Article
Cancer cells are able to elaborate enzymatic mechanisms allowing tumors to resist or escape imune rejection. Among the enzymes involved, indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that initiates the first and rate-limiting step of tryptophan breakdown along the kynurenine pathway, has emerged as a promising molecular target for the development of new immunotherapeutic anticancer agents. This review summarizes the synthesis and IDO activities of the different classes of marine and other inhibitors reported so far.
 
Article
There is increasing evidence of the potential therapeutic utility of glutamate receptor antagonists in the treatment of several neurodegenerative disorders, including stroke and epilepsy. In the last few years noncompetitive AMPA receptor antagonists have received considerable attention due to their therapeutic potentiality. The discovery of GYKI 52466, the prototype of noncompetitive AMPA receptor antagonists endowed with anticonvulsant and neuroprotective properties, induced growing interest on 2,3-benzodiazepine derivatives. This review covers the chemistry and pharmacology of this important class of AMPA receptor antagonists.
 
Article
5-Aryl-pyrrolo[2,3-d]pyrimidines incorporating different N(7)-substituents have been prepared and evaluated for their inhibitory potency towards the tyrosine kinase c-Src. Optimization of these compounds resulted in highly potent c-Src inhibitors, some (e.g. 4g, 6g, 7h, 8l) with excellent specificity towards other receptor and nonreceptor tyrosine kinases. In addition compounds 4g, 5b and 5c are characterized by a good pharmacokinetic profile.
 
Article
Solid-phase organic synthesis of heterocyclic compounds on solid-support has been a focus of recent investigations because of the potential applicability of these compounds toward a variety of drug targets. Among the various heterocycles, we have been especially interested in quinazoline-2,4-diones because of the wide range of their bioactivities. Therefore, in this article we review methods for the solid-phase synthesis of quinazoline-2,4-diones and their analogues. Since all of these heterocycles can be speedily derivatized from resin-bound primary amines, incorporating the amines at the 3N-position of quinazoline-2,4-diones or corresponding positions of its analogues, it becomes possible to efficiently compare the bioactivities of these quinazoline-2,4-diones and their analogues. Various methods of solid-phase synthesis described herein should be practical and useful tools for the medicinal chemist in supporting drug discovery initiatives.
 
General structure of 2,5-diketopiperazines. 
In Vitro Neuroprotective Activity of DKPs 4-6 [29] In vitro models 
Article
2,5-diketopiperazines are the simplest cyclic peptides found in nature, commonly biosynthesized from amino acids by different organisms, and represent a promising class of biologically active natural products. Their peculiar heterocyclic structure confers high stability against the proteolysis and constitutes a structural requirement for the active intestinal absorption. Furthermore, the diketopiperazine-based motif is considered as a novel brain shuttle for the delivery of drugs with limited ability to cross the blood-brain barrier (BBB) and can be proposed as an ideal candidate for the rational development of new therapeutic agents. Although these cyclic peptides have been known since the beginning of the 20th century, only recently have they attracted substantial interest with respect to the wide spectrum of their biological properties, including antitumor, antiviral, antifungal, antibacterial and antihyperglycemic activities. In addition to these, the most challenging function of the diketopiperazine derivatives is related with their remarkable neuroprotective and nootropic activity. The aim of the present paper is to provide an overview of the two major classes of diketopiperazines, the TRH-related and the unsaturated derivatives both characterized by a significant ability to protect against neurotoxicity in several experimental models. The neuroprotective profile of these compounds suggests that they may have a future utility in the therapy of neuronal degeneration in vivo, potentially through several different mechanisms.
 
Article
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. Therefore, it is important to be acquainted with these new structures as well as their syntheses. To these ends, this review covers the syntheses of 28 NCEs marketed in 2002.
 
Article
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing new future drugs. To these ends, this review covers the syntheses of 23 NCEs marketed in 2003.
 
Article
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as leads for designing future drugs. To this end, this review covers the syntheses of 12 NCEs marketed in 2004.
 
Article
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. To these ends, this review covers the syntheses of 22 NCEs marketed in 2005.
 
Article
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. To these ends, this review covers the syntheses of 16 NCEs marketed in 2006.
 
Top-cited authors
Miguel López-Lázaro
  • Universidad de Sevilla
Mercedes Gonzalez
  • Universidad de la República de Uruguay
Carlos Alberto Manssour Fraga
  • Federal University of Rio de Janeiro
Eliezer Barreiro
  • Federal University of Rio de Janeiro
Dinorah Gambino
  • Universidad de la República de Uruguay