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Terminal deoxynucletidyl transferase (TdT) is overexpressed in some cancer types, where it might compete with pol μ during the mutagenic repair of double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. Here we report the discovery and characterization of pyrrolyl and indolyl diketo acids that specifically target TdT and behave as nucleotide-competitive inhibitors. These compounds show a selective toxicity toward MOLT-4 compared to HeLa cells that correlate well with in vitro selectivity for TdT. The binding site of two of these inhibitors was determined by cocrystallization with TdT, explaining why these compounds are competitive inhibitors of the deoxynucleotide triphosphate (dNTP). In addition, because of the observed dual localization of the phenyl substituent, these studies open the possibility of rationally designing more potent compounds.

Pharmacophoric mapping is a useful procedure to frame, especially when crystallographic receptor structures are unavailable as in ligand-based studies, the hypothetical site of interaction. In this study, 71 pyrrole derivatives active against M. tuberculosis were used to derive through a recent new 3-D QSAR protocol, 3-D QSAutogrid/R, several predictive 3-D QSAR models on compounds aligned by a previously reported pharmacophoric application. A final multiprobe (MP) 3-D QSAR model was then obtained configuring itself as a tool to derive pharmacophoric quantitative models. To stress the applicability of the described models, an external test set of unrelated and newly synthesized series of R-4-amino-3-isoxazolidinone derivatives found to be active at micromolar level against M. tuberculosis was used, and the predicted bioactivities were in good agreement with the experimental values. The 3-D QSAutogrid/R procedure proved to be able to correlate by a single multi-informative scenario the different activity molecular profiles thus confirming its usefulness in the rational drug design approach.

The antiparasitic activity of azole and new 4-aminopyridine derivatives has been investigated. The imidazoles 1 and 3-5 showed a potent in vitro antichagasic activity with IC50 values in the low nanomolar concentration range. The (S)-1, (S)-3, and (S)-5 enantiomers showed (up to) a thousand-fold higher activity than the reference drug benznidazole and furthermore low cytotoxicity on rat myogenic L6 cells.

Since the discovery of the serotonin 4 receptor (5-HT(4)R), a large number of receptor ligands have been studied. The safety concerns and the lack of market success of these ligands have mainly been attributed to their lack of selectivity. In this study we describe the discovery of N-[(4-piperidinyl)methyl]-1H-indazole-3-carboxamide and 4-[(4-piperidinyl)methoxy]-2H-pyrrolo[3,4-c]quinoline derivatives as new 5-HT(4)R ligands endowed with high selectivity over the serotonin 2A receptor and human ether-a-go-go-related gene potassium ion channel. Within these series, two molecules (11 ab and 12 g) were identified as potent and selective 5-HT(4)R antagonists with good in vitro pharmacokinetic properties. These compounds were evaluated for their antinociceptive action in two analgesia animal models. 12 g showed a significant antinociceptive effect in both models and is proposed as an interesting lead compound as a 5-HT(4)R antagonist with analgesic action.

Chemical manipulations undertaken on some bis(bromo- and dibromo-phenol) compounds previously reported by us as wide-spectrum epigenetic inhibitors let us to identify bis (bromo- and dibromo-methoxyphenyl) derivatives highly selective for PR-SET7 and EZH2 (compounds 4, 5, 9, and 10). Western blot analyses were carried out in U937 cells to determine the effects of such compounds on the methyl marks related to the tested enzymes (H3K4me1, H3K9me2, H4H20me1, and H3K27me3). The 1,5-bis(3-bromo-4-methoxyphenyl)penta-1,4-dien-3-one 4 (EC(50) vs EZH2 = 74.9 μM), tested in U937 cells at 50 μM, induced massive cell death and 28% of granulocytic differentiation, highlighting the potential use of EZH2 inhibitors in cancer., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Dyes like CR are able to inhibit the aggregation of Aβ fibrils. Thus, a screening of a series of dyes including ABBB (1) was performed. Its main component 2 tested in an in vitro assay (i.e., ThT assay) showed good potency at inhibiting fibrils association. Congeners 4-9 have been designed and synthesized as inhibitors of Aβ aggregation. A number of these newly synthesized compounds have been found to be active in the ThT assay with IC(50) of 1-57.4 μM. The most potent compound of this series, 4k, showed micromolar activity in this test. Another potent derivative 4q (IC(50) = 5.6 μM) rapidly crossed the blood-brain barrier, achieving whole brain concentrations higher than in plasma. So 4q could be developed to find novel potent antiaggregating βA agents useful in Alzheimer disease as well as other neurological diseases characterized by deposits of amyloid aggregates.

A set of polyphenol compounds was synthesized and assayed for their ability in inhibiting influenza A virus replication. A sub-set of them showed low toxicity. The best compounds within this sub-set were 4 and 6g, which inhibited the viral replication in a dose-dependent manner. The antiviral activity of these molecules was demonstrated to be caused by their interference with intracellular pathways exploited for viral replication: (1) MAP kinases controlling nuclear-cytoplasmic traffic of viral ribonucleoprotein complex; (2) redox-sensitive pathways, involved in maturation of viral hemagglutinin protein., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A new series of aromatic ester and carbamate derivatives of 2-(1H-imidazol-1-yl)-1-phenylethanol were synthesized and evaluated for their antifungal activity towards Candida albicans and non-albicans Candida species strains. The aromatic biphenyl ester derivatives 6a-c were more active than the reference compound fluconazole. 6c possesses a MIC mean values of 1.7 ± 1.4 μg mL(-1)vs C. albicans and 1.9 ± 2.0 μg mL(-1)vs non-albicans Candida species strains. The racemic mixtures of 6a, b were purified to afford the pure enantiomers. The (-) isomers were up to 500 times more active than (+) isomers. (-)-6a and (-)-6b were thirty and ninety times more active than fluconazole towards C. krusei strain respectively. The racemates of 6a-c showed low cytotoxicity against human monocytic cell line (U937) with 6a demonstrating a CC(50) greater than 128 μg mL(-1)., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections including HIV-1. Despite more than two decades of HIV-1 research, there is still no efficacious HIV-1 vaccine, and the scientific community appears sceptical about the short or long-term feasibility of developing a vaccine that has the ability to induce sterilizing immunity against HIV-1. In this setting, microbicide research has been developed. Among the promising candidate microbicides, the integrase inhibitors are the most recently developed compounds. In fact, since the beginning reverse transcriptase, fusion and entry inhibitors were identified as possible HIV-specific candidate microbicides along with the non-specific topical microbicides. In the case of integrase inhibitors, only a few have demonstrated to block HIV-1 infection in models that mimic sexual transmission of the virus. These compounds have been tested in in vitro and ex vivo assays to determine their efficacy in pre- and/or post-exposure prophylactic settings. In particular, the naphthyridinecarboxyamide L-870,812 has been shown to block viral infection in pre- and post-exposure studies obtaining comparable results to the reverse transcriptase inhibitor PMPA. The purpose of this article is to provide an overview of integrase inhibitors as potential topical microbicides and their comparative evaluation with HIV-specific and non-specific microbicides.

Coactivator-associated arginine methyltransferase 1 (CARM1) represents a valuable target for hormone-dependent tumors such as prostate and breast cancers. Here we report the enzyme and cellular characterization of the 1-benzyl-3,5-bis(3-bromo-4-hydroxybenzylidene)piperidin-4-one (7g) and its analogues 8a-l. Among them, 7g, 8e, and 8l displayed high and selective CARM1 inhibition, with lower or no activity against a panel of different PRMTs or HKMTs. In human LNCaP cells, 7g showed a significant dose-dependent reduction of the PSA promoter activity.

Macrophages represent an important site for productive infection of HIV-1 and the evaluation of integrase (IN) inhibitors on this cell subset is of fundamental importance. In this report, preclinical evaluation of IN inhibitors on primary human macrophages was attempted successfully using a 96-well microtiter phenotypic assay developed recently for the evaluation of IN inhibitors in a cell-based system by taking advantage of HIV-derived lentiviral vectors expressing luciferase. IN inhibitors were also tested using a lentiviral vector containing an IN with introduced T66I/S153Y mutations, known to affect the activity of azido-group-containing diketo acid (DKA) IN inhibitors. Utilizing different classes of HIV integrase inhibitors against the wild-type IN and the mutant mentioned above, some of the IN inhibitors used were also active on this particular mutant, suggesting that should HIV-1 develop additional or different mutations to become resistant to such anti-IN drugs, new drugs can be developed with a better resistance profile. This assay provides a standardized method for the preclinical evaluation of the efficacy of IN inhibitors on wild-type and mutated IN that can be adapted easily for the evaluation of anti-IN activity on IN sequences derived from patients., (Copyright 2010 Elsevier B.V. All rights reserved.)

Fungi have emerged worldwide as increasingly frequent causes of healthcare-associated infections, but fungal infections have generally been considered curable, and thus the demand for new antifungal agents has been very low. Although superficial fungal infections of the skin and nails are common and are for the most part treated successfully with existing antifungal agents, serious fungal infections are becoming a growing danger for human health. This is particularly true for AIDS patients, but also for recipients of transplants, and users of antineoplastic agents, corticoids, and even antibiotics. A major problem is the increasing emergence of resistance to antimycotic agents, and since azoles--the most used class of antifungals--suffer a significant incidence of resistance, new efforts are now devoted to the discovery of new agents with different mechanisms of action. Not so long ago, combinatorial chemistry appeared to be the future for drug discovery, but in the late 1990s synthetic chemists realized that combinatorial libraries lacked the "complexity" usually associated with natural compounds. Research into biologically active natural products has thus had a reprise, in particular with the advent of the concept of diversity-oriented synthesis. This review reports what is so far known about natural products as antifungal agents, and provides an overview of natural compounds with both known and unknown mechanisms of action.

Different liquid chromatographic/tandem mass spectrometric (LC/MS/MS) scanning techniques were considered for the characterization of tamoxifene metabolites in human urine for anti-doping purpose. Five different LC/MS/MS scanning methods based on precursor ion scan (precursor ion scan of m/z 166, 152 and 129) and neutral loss scan (neutral loss of 72 Da and 58 Da) in positive ion mode were assessed to recognize common ions or common losses of tamoxifene metabolites. The applicability of these methods was checked first by infusion and then by the injection of solution of a mixture of reference standards of four tamoxifene metabolites available in our laboratory. The data obtained by the analyses of the mixture of the reference standards showed that the five methods used exhibited satisfactory results for all tamoxifene metabolites considered at a concentration level of 100 ng/mL, whereas the analysis of blank urine samples spiked with the same tamoxifene metabolites at the same concentration showed that the neutral loss scan of 58 Da lacked sufficient specificity and sensitivity. The limit of detection in urine of the compounds studied was in the concentration range 10-100 ng/mL, depending on the compound structure and on the selected product ion. The suitability of these approaches was checked by the analysis of urine samples collected after the administration of a single dose of 20 mg of tamoxifene. Six metabolites were detected: 4-hydroxytamoxifene, 3,4-dihydroxytamoxifene, 3-hydroxy-4-methoxytamoxifene, N-demethyl-4-hydroxytamoxifene, tamoxifene-N-oxide and N-demethyl-3-hydroxy-4-methoxytamoxifene, which is in conformity to our previous work using a time-of-flight (TOF) mass spectrometer in full scan acquisition mode., (Copyright (c) 2010 John Wiley & Sons, Ltd.)

Second-order rate constants of the diethylamine-promoted enantiomerization of 2-[2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-1-phenylethyl]-isoindole-1,3-dione, a chiral alpha-substituted ketone endowed with high anti-MAO activity type-A, were measured by dynamic high-performance liquid chromatography (DHPLC), stopped-flow high-performance liquid chromatography (sf-HPLC), and a classical method based on enantioselective HPLC as the monitoring tool. The chiral column used in all determinations was the commercial Chiralpak AD. By comparison of the obtained data, perturbing effects of the stationary phase on the DHPLC and sf-HPLC determinations were highlighted and distinguished in indirect (SP(IPC)) and direct (SP(DPC)) type. It was evidenced that SP(DPC) noise effects may be completely erased by simple mathematical treatment of data obtained at different concentrations of the basic catalyst. Perturbations of type SP(IPC) may instead only be partially kept down by modulating the concentration of the basic catalyst. An estimation of the density distribution of catalytic sites covalently bonded to the stationary phase (SP) of the Chiralpak AD was performed exploiting the quantified SP(DPC) effects. Such an approach might be of general application, supplying a useful way to characterize the attitude of SPs to speed acid- or base-catalyzed equilibria possibly active during chromatographic separations.

An effective strategy to assess and modulate the stereolability of chiral alpha substituted ketones (C alpha SKs) is presented. The tendency of C alpha SKs to retain or change their configuration in water is analyzed as a function of thermodynamic proton-release attitude of alpha asymmetric atoms inside the structures by linear Brønsted correlations. A molecular modeling procedure was developed to analyze and suggest chemical modifications of C alpha SKs in view to obtain the desired grade of stereochemical stability. The approach was employed to predict the tendency to enantiomerize in water of two ketones (1 and 2) endowed with inhibitory activity against monoamine oxidases (MAOs) and the results were confirmed by experimental kinetics measurements performed in organic medium. As a demonstration of practical potentialities of the approach, four new structures, conceived as simple chemical modifications of 1 and 2, were designed to improve/reduce the stereostability grade of the starting anti-MAO ketones. The possibility to extend easily the procedure to other classes of C-H acids appears of interest.

Novel quinolinonyl diketo acids were designed to obtain integrase (IN) inhibitors selectively active against the strand transfer (ST) step of the HIV integration process. Those new compounds are characterized by a single aryl diketo acid (DKA) chain in comparison to 4, a bifunctional diketo acid reported by our group as an anti-IN agent highly potent against both the 3'-processing and ST steps. Compound 6d was the most potent derivative in IN enzyme assays, while 6i showed the highest potency against HIV-1 in acutely infected cells. The selective inhibition of ST suggested the newly designed monofunctional DKAs bind the IN-DNA acceptor site without affecting the DNA donor site.

Conceptually, blocking human immunodeficiency virus type 1 (HIV-1) integration is the last possibility for preventing irreversible cellular infection. Using cocultures of monocyte-derived dendritic cells and CD4(+) T cells, which represent primary targets in sexual transmission, we demonstrated that blocking integration with integrase strand transfer inhibitors (InSTIs), particularly L-870812, could consistently block cell-free and cell-associated HIV-1 infection. In a pretreatment setting in which the compound was present before and during infection and was afterwards gradually diluted during the culture period, the naphthyridine carboxamide L-870812 blocked infection with the cell-free and cell-associated HIV-1 Ba-L strain at concentrations of, respectively, 1,000 and 10,000 nM. The potency of L-870812 was similar to that of the nucleotide reverse transcriptase inhibitor R-9-(2-phosphonylmethoxypropyl) adenine (PMPA) but one or two orders of magnitude lower than those of the nonnucleoside reverse transcriptase inhibitors UC781 and TMC120. In contrast, the diketo acid RDS derivative InSTIs showed clear-cut but weaker antiviral activity than L-870812. Moreover, L-870812 completely blocked subtype C and CRFO2_AG primary isolates, which are prevalent in the African heterosexual epidemic. Furthermore, the addition of micromolar concentrations of L-870812 even 24 h after infection could still block both cell-free and cell-associated Ba-L, opening the prospect of postexposure prophylaxis. Finally, an evaluation of the combined activity of L-870812 with either T20, zidovudine, PMPA, UC781, or TMC120 against replication-deficient HIV-1 Ba-L (env) pseudovirus suggested synergistic activity for all combinations. Importantly, compounds selected for the study by using the coculture model were devoid of acute or delayed cytotoxic effects at HIV-blocking concentrations. Therefore, these findings provide evidence supporting consideration of HIV-1 integration as a target for microbicide development.

Similar to other retroviruses, productive infection with HIV-1 requires three key steps in the viral replication: (i) reverse transcription of viral genomic RNA into viral cDNA by the viral reverse transcriptase; (ii) integration of viral cDNA into host cell genome using the viral integrase; and (iii) cleavage of newly synthesized viral polypeptide by the viral protease into individual viral proteins during new virion assembly. Following their discovery, all three viral enzymes were considered as targets for antiretroviral drugs. However, while multiple reverse transcriptase and protease inhibitors have been used for more than 12 years to treat HIV-infected individuals, only recently has the viral integrase enzyme emerged as an alternative, clinically validated target to block HIV-1 replication. Here we review the biology of HIV-1 integration, the mechanisms of action and development of resistance to integrase inhibitors, and the latest data on the most recent clinical trials involving this promising, novel class of antiretroviral drugs.

( R)-(-)- and ( S)-(+)-1-(1-[ (11)C]methyl-1 H-pyrrol-2-yl)-2-phenyl-2-(1-pyrrolidinyl)ethanone 4 and 5 were synthesized, and their properties as tracers for positron emission tomography (PET) studies of monoamine oxidase type A (MAO-A) in the brain of living pigs were tested. Parametric maps of the distribution volume ( V d) 4 in pig brain were qualitatively similar to those obtained with [ (11)C]harmine, with prominent binding in the ventral forebrain and mesencephalon. Its binding was highly vulnerable to MAO blockade, suggesting a binding potential as high as 2 for MAO-A sites. The slow plasma metabolism of 4 and 5 may present advantages over [ (11)C]harmine for routine PET studies of MAO-A.

Cinnamoly compounds 1a-c and 2a-d were designed, synthesized, and in vitro tested as p300 inhibitors. At different degrees, all tested compounds were proven to inactivate p300, particularly, derivative 2c was the most active inhibitor, also showing high specificity for p300 as compared to other histone acetyltransferases. Most notably, 2c showed anti-acetylase activity in mammalian cells. These compounds represent a new class of synthetic inhibitors of p300, characterized by simple chemical structures.

Background: The discovery of diketoacid-containing derivatives as inhibitors of HIV-1 Integrase (IN) (IN inhibitors, IINs) has played a major role in validating this enzyme as an important target for antiretroviral therapy. Since the in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether the IINs are recognized by the multidrug transporter MDR1-P-glycoprotein (P-gp) thereby reducing their intracellular accumulation. To address the effect of IINs on drug transport, nine quinolonyl diketo acid (DKA) derivatives active on the HIV-1 IN strand transfer (ST) step and with EC50 ranging from 1.83 to >50 mum in cell-based assays were tested for their in vitro interaction with P-gp in the CEM-MDR cell system. IINs were investigated for the inhibition and induction of the P-gp function and expression as well as for multidrug resistance (MDR) reversing ability., Results: The HIV-1 IINs act as genuine P-gp substrates by inhibiting doxorubicin efflux and inducing P-gp functional conformation changes as evaluated by the modulation of UIC2 mAb epitope. Further, IINs chemosensitize MDR cells to vinblastine and induce P-gp expression in drug sensitive revertants of CEM-MDR cells., Conclusion: To our knowledge, this is the first demonstration that HIV-1 IINs are P-gp substrates. This biological property may influence the absorption, distribution and elimination of these novels anti HIV-1 compounds.

HIV-1 integrase binds site-specifically to the ends of the viral cDNA. We used two HIV-1 integrase-DNA cross-linking assays to probe the binding sites of integrase inhibitors from different chemical families and with different strand transfer selectivities. The disulfide assay probes cross-linking between the integrase residue 148 and the 5'-terminal cytosine of the viral cDNA, and the Schiff base assay probes cross-linking between an integrase lysine residue and an abasic site placed at selected positions in the viral cDNA. Cross-linking interference by eight integrase inhibitors shows that the most potent cross-linking inhibitors are 3'-processing inhibitors, indicating that cross-linking assays probe the donor viral cDNA (donor binding site). In contrast, strand transfer-selective inhibitors provide weak cross-linking interference, consistent with their binding to a specific acceptor (cellular DNA) site. Docking and crystal structure studies illustrate specific integrase-inhibitor contacts that prevent cross-linking formation. Four inhibitors that prevented Schiff base cross-linking to the conserved 3'-terminal adenine position were examined for inhibition at various positions within the terminal 21 bases of the viral cDNA. Two of them selectively inhibited upper strand cross-linking, whereas the other two had a more global effect on integrase-DNA binding. These findings have implications for elucidating inhibitor binding sites and mechanisms of action. The cross-linking assays also provide clues to the molecular interactions between integrase and the viral cDNA.

Novel arylthio isopropyl pyridinylmethylpyrrolemethanol (AThP) derivatives 3-5, which are related to capravirine (S-1153), were synthesized and tested for their ability to block the replication cycle of HIV-1 in infected cells. The newly synthesized AThPs are active in the concentration range of 0.008-53 microM. Even if compounds 3-5 are generally less potent than S-1153, their SI values are in some cases similar to that of the reference drug. In fact, the cytotoxicities of AThPs are generally lower than that of S-1153. Compound 4e was the most active derivative of this series in cell-based assays; its potency is similar to that of S-1153 (EC(50)=8 and 3 nM, respectively), as is its selectivity index (SI=6250 and 7000, respectively). AThP derivatives were proven to target HIV-1 RT. In fact, compounds 3-5 generally inhibited the viral enzyme at concentrations similar to those observed in cell-based assays. A selected number of AThPs (4k and 5a,e) were tested against clinically relevant drug-resistant forms of recombinant reverse transcriptase (rRT) carrying the K103N and Y181I mutations. Carbamate 5e showed an approximate 240-fold decrease in activity against Y181I, but only a 10-fold loss in potency against the K103N rRT form. Docking calculations were also performed to investigate the binding mode of compounds 2, 4e, 4j, 4k and 5e into the non-nucleoside binding site of HIV-1 RT and to rationalize some structure-activity relationships and resistance data.

Arylthio isopropyl pyridinylmethylpyrrolemethanols (AThPs) have been recently reported as a new class of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors acting at the non-nucleoside binding site (NNBS) of this enzyme. Docking experiments of the potent inhibitors 4k (IC(50) = 0.24 microM, SI = 167) and 5e (IC(50) = 0.11 microM, SI > 1667) of wild-type RT prompted the synthesis and biological evaluation of novel AThP derivatives featuring a number of polar groups in position 3 of the pyrrole ring and larger and more hydrophobic alicyclic substituents in place of the isopropyl group at position 4. Among the compounds synthesized and tested in cell-based assays against HIV-1 infected cells, 19b was the most active, with EC(50) = 0.007 microM, CC(50) = 114.5 microm, and SI = 16357. This compound and its precursor 18b retained interesting activities against clinically relevant drug-resistant RT forms carrying K103N, Y181I, and L100I mutations. Docking calculations of 10, 14, 18b, and 19b were also performed to investigate their binding mode into the RT NNBS and to rationalize both structure-activity relationship and resistance data.

Therapeutic strategies aimed at inhibiting human immunodeficiency virus type 1 (HIV-1) replication employ a combination of drugs targeted to two viral enzymes (reverse transcriptase and protease) and to the viral entry/fusion step. However, the high propensity of HIV-1 to develop resistance makes the development of novel compounds targeting different steps of the HIV-1 life cycle essential. Among these, integrase (IN) inhibitors have successfully passed the early phases of clinical development. By preventing integration, IN inhibitors preclude viral replication while allowing production of extrachromosomal forms of viral DNA (E-DNA). Here, we describe an improved and standardized assay aimed at evaluating IN inhibitors by taking advantage of the transcriptional activity of E-DNA produced by HIV-derived vectors in the absence of replication-competent virus. In this context, the use of the firefly luciferase gene as a reporter gene provides a rapid and quantitative measure of viral-vector infectivity, thus making it a safe and cost-effective assay for evaluating novel IN inhibitors.

The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the beta-diketo acids (DKAs) represent a major lead for anti-HIV-1 drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized, and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3'-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-cross-linking experiments.

TIBO- and TBO-like sulfone derivatives 1 and 2 were designed, synthesized, and tested for their ability to block the replication cycle of HIV-1 in infected cells. The anti-HIV-1 activities of sulfones 3, which were intermediates in the syntheses of 1 and 2, were also evaluated. Surprisingly, the sulfone analogues of TIBO R82913 (compounds 1) were inactive, whereas interesting results were obtained for truncated derivatives 2. Compound 2 w was the most potent among this series in cell-based assays (EC50=0.07 microM, CC50>200 microM, SI>2857). It was twofold less potent than R82913, but more selective. An X-ray crystallographic analysis was carried out to establish the absolute configuration of 2 w and its enantiomer 2 x, which were obtained by semipreparative HPLC of 2 v, one of the most potent racemates. Compounds 1-3 were proven to target HIV-1 RT. In fact, representative derivatives inhibited recombinant HIV-1 RT in vitro at concentrations similar to those active in cell-based assays. 3D QSAR studies and docking simulations were developed on TIBO- and TBO-like sulfone derivatives to rationalize their anti-HIV-1 potencies and to predict the activity of novel untested sulfone derivatives. Predictive 3D QSAR models were obtained with a receptor-based alignment by docking of TIBO- and TBO-like derivatives into the NNBS of RT.

Mammalian terminal deoxyribonucleotidyl transferase (TDT) catalyzes the non-template-directed polymerization of deoxyribonucleoside triphosphates and has a key role in V(D)J recombination during lymphocyte and repertoire development. Over 90% of leukemic cells in acute lymphocytic leukemia and approximately 30% of leukemic cells in the chronic myelogenous leukemia crisis show elevated TDT activity. This finding is connected to a poor prognosis and response to chemotherapy and reduced survival time. On the other hand, recent data indicated that TDT is not the only terminal deoxyribonucleotidyl transferase in mammalian cells. Its close relative, DNA polymerase (pol) pol lambda can synthesize DNA both in a template dependent (DNA polymerase) and template-independent (terminal deoxyribonucleotidyl transferase) fashion. Pol lambda might be involved in the nonhomologous end-joining (NHEJ) recombinational repair pathway of DNA double strand breaks (DSBs). Specific inhibitors of these enzymes hold the potential to be developed into a novel class of antitumoral agents. In this review, we will summarize the recent advances in the synthesis and characterization of the first classes of specific inhibitors of mammalian terminal transferases and their potential applications.

A molecular modeling strategy using aryl diketo acid (ADK) derivatives recently reported in the literature as hepatitis C virus (HCV) polymerase inhibitors was designed. A 3D chemical-feature-based pharmacophore model was developed using Catalyst software, which produced 10 pharmacophore hypotheses. The top-ranked one (Hypo 1), characterized by a high correlation coefficient (r = 0.965), consisted of two hydrogen bond acceptors, one negative ionizable moiety, and two hydrophobic aromatics. This model was used to predict the anti-RNA-dependent RNA polymerase (anti-RdRp) activity of 6-(1-arylmethylpyrrol-2-yl)-1,4-dioxo-5-hexenoic acids and other ADK derivatives previously synthesized in our laboratories as HIV-1 integrase inhibitors. Furthermore, the experimental IC50 values of 9 compounds, tested in vitro against recombinant HCV polymerase, were compared with the corresponding values predicted using Hypo1. A good agreement between experimental and simulated data was obtained. The results demonstrate that the hypothesis derived in this study can be considered to be a useful tool in designing new leads based on ADK scaffolds as HCV RdRp inhibitors.

1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives are reported. The newly synthesized azoles were tested against 12 strains of Candida albicans together with bifonazole, miconazole, itraconazole, fluconazole, and compounds 1a, 1b, 3a, 3b, and 3c used as reference drugs. In general, tested derivatives showed good antifungal activities, and the most potent compound was 1d (MIC(90) = 0.032 microg/mL), which was from 4- to 250-fold more potent than reference drugs. Catalyst software was applied to develop a quantitative pharmacophore model to be used for the rational design of new antifungal azoles. Some key interactions, as well as excluded volumes, further to the coordination bond of azole antifungals with the demethylase enzyme, are highlighted.

Mammalian terminal deoxyribonucleotidyl transferase (TDT) catalyzes the non-template-directed polymerization of deoxyribonucleoside triphosphates and has a key role in V(D)J recombination during lymphocyte and repertoire development. More than 90% of leukemic cells in acute lymphocytic leukemia and approximately 30% of leukemic cells in the chronic myelogenous leukemia crisis show elevated TDT activity. This finding is connected to a poor prognosis and response to chemotherapy and reduced survival time. On the other hand, recent data indicated that TDT is not the only terminal deoxyribonucleotidyl transferase in mammalian cells. Its close relative, DNA polymerase lambda, can synthesize DNA both in a template-dependent (polymerase) and template-independent (terminal deoxyribonucleotidyl transferase) fashion. DNA polymerase lambda might be involved in the nonhomologous end-joining recombinational repair pathway of DNA double-strand breaks. In this work, we report the characterization of the mechanism of action of three diketo hexenoic acid (DKHA) derivatives, which proved to be extremely selective for the terminal deoxyribonucleotidyl transferase activity of DNA polymerase lambda and TDT. They seem to be the first non-nucleoside-specific inhibitors of mammalian terminal transferases reported. Moreover, the DKHA analog 6-(1-phenylmethyl-1H-indol-3-yl)-2,4-dioxo-5-hexenoic acid (RDS2119) was not toxic toward HeLa cells (CC(50) > 100 muM), whereas it showed significant cytotoxicity against the TDT(+) leukemia cell line MOLT-4 (CC(50) = 14.9 muM), thus having the potential to be further developed as a novel antitumor agent.

Pyrrolylethanoneamines 1-12, 18-23 and related amino alcohols 13-15, 24-27 were synthesized and tested against monoamine oxidases A and B (MAO-A and MAO-B) enzymes. In general, aminoketones 1-12, 18-23 were found to be potent and selective MAO-A inhibitors. In particular, 18 was more potent and selective against the MAO-A isoenzyme than reference drugs. Interestingly, amino alcohol 25 selectively inhibited MAO-B enzyme and could be a lead compound for designing more potent and selective MAO-B inhibitors.

A number of 2H-pyrrolo[3,4-b] [1,5]benzothiazepine derivatives (PBTAs) 7-25 and the related synthetic intermediates 3-pyrrolyl aryl sulfones (PASs) 26-32 were designed, synthesized and tested as potential anti-HIV-1 agents targeted at the reverse transcriptase (RT). The PBTAs were conceived as tricyclic analogs of nevirapine, pyrrolo[1,2-b] [1,2,5]benzothiadiazepine 5 (PBTD) and pyrrolo[2,1-d] [1,2,5]benzothiadiazepine 6, NNRTIs endowed with potent anti-HIV-1 activities. The majority of tested PBTAs were active against HIV-1-induced cytopathicity in MT-4 cells at concentrations ranging from 0.3 to 40 microM. In particular, compound 10 was the most potent derivative with EC50 = 0.3 microM, comparable to that of nevirapine used as reference drug. In the 3-pyrrolyl aryl sulfones (26-32) series only three sulfones were found active against HIV-1 replication cycle. The following preliminary SAR could be depicted for the title derivatives: i) the conformationally restrained PBTAs are more potent than the corresponding open counterparts (PASs); ii) the DMA group give the highest anti-HIV-1 potency in the PBTAs series; iii) PBTAs and the corresponding thiones are equipotent; iv) an unsubstituted amino group, as part of p-chloroanilino moiety, is a strong determinant for the antiviral activity in the PASs series. The most potent derivatives in cell-based assays were proven to target the RT in enzyme assays. Unfortunately, none of the test compounds inhibited the multiplication of clinically relevant drug-resistant viruses (mutants of HIV-1 carrying K103N and Y181C mutations) at concentrations lower than 30 microM. However, the good results obtained against replication of wt HIV-1, lead us to consider compound 10 as a lead compound for further investigation in this field. In particular, our efforts will be directed to modifications of 10 devoted to obtain new derivatives active against HIV-1 mutant strains.

Highly active anti-retroviral therapy (HAART) using reverse transcriptase (RT) and protease (PR) inhibitors and, more recently, inhibitors of the fusion is currently the best clinical approach in combating acquired immunodeficiency syndrome (AIDS), caused by infection from human immunodeficiency virus type 1 (HIV-1). However, this therapy does not completely eradicate the virus, so that resistant strains easily emerge. The above problem calls urgently for research on inhibitors of further viral targets such as integrase (IN), the third enzyme produced by HIV. Recently, our research group was engaged in studies on conformationally restrained cinnamoyl compounds related to curcumin as anti-IN agents. Compounds containing both a 3,4,5-trihydroxyphenyl group and a carboxylic acid function were potent IN inhibitors active against viral replication. More recently, a promising new class of inhibitors synthesized by Merck Company has emerged, which contain aryldiketoacid (ADK) functionality. The ADKs selectively inhibited the stand transfer (ST) step of integration and were proven to be effective IN inhibitors in vivo. Our interest in the field of IN inhibitors led us to design pyrrole and indole derivatives containing both a cinnamoyl moiety and a diketoacid group. A number of the cited derivatives were proven potent IN inhibitors, which selectively inhibited the ST step at submicromolar concentrations and were effective against virus replication in HIV-1 infected cells.

The human immunodeficiency virus-type 1 (HIV-1) reverse transcriptase (RT) is a multifunctional enzyme which displays DNA polymerase activity, which recognizes RNA and DNA templates, and a degradative ribonuclease H (RNase H) activity. While both RT functions are required for retroviral replication, until now only the polymerase function has been widely explored as drug target. We have identified a novel diketo acid derivative, 6-[1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester (RDS 1643), which inhibits in enzyme assays the HIV-1 RT-associated polymerase-independent RNase H activity but has no effect on the HIV-1 RT-associated RNA-dependent DNA polymerase (RDDP) activity and on the RNase H activities displayed by the Avian Myeloblastosis Virus and E. coli. Time-dependence studies revealed that the compound is active independently on the order of its addition to the reaction mixture, and inhibition kinetics studies demonstrated that RDS 1643 inhibits the RNase H activity noncompetitively, with a K(I) value of 17 microM. When RDS 1643 was combined with non-nucleoside RT inhibitors (NNRTI), such as efavirenz and nevirapine, results indicated that RDS 1643 does not affect the NNRTIs anti-RDDP activity and that, vice versa, the NNRTIs do not alter the RNase H inhibition by RDS 1643. When assayed on the viral replication in cell-based assays, RDS 1643 inhibited the HIV-1(IIIB) strain with an EC(50) of 14 microM. Similar results were obtained against the Y181C and Y181C/K103N HIV-1 NNRTI resistant mutant strains. RDS 1643 may be the first HIV-1 inhibitor selectively targeted to the viral RT-associated RNase-H function.

A series of 6-aryl-2,4-dioxo-5-hexenoic acids, were synthesized and tested against HIV-1 in cell-based assays and against recombinant HIV-1 integrase (rIN) in enzyme assays. Compound 8a showed potent antiretroviral activity (EC(50)=1.5 microM) and significant inhibition against rIN (strand transfer: IC(50)=7.9 microM; 3'-processing: IC(50)=7.0 microM). A preliminary molecular modeling study was carried out to compare the spatial conformation of 8a with those of L-731988 (4) and 5CITEP (7) in the IN core.

A series of N-aryl heteroarylisopropanolamines in which an indole or a 3-arylpyrrole moiety was linked to an aryl group through an isopropanolamine linker, were designed and synthesized as potential anti-HIV-1-PR agents. Series was tested for their ability in blocking PR activity. As a rule, indole derivatives of class 1 exhibited more potency than pyrrole analogues of class 2 while tert-butylamide substituents increased anti-PR potency. In fact, bis tert-butylamide 1e showed the highest activity with IC(50)=25 microM. Even if not very potent, a simple class of anti-PR agents, with a facile synthetic pathway was discovered. QSAR studies on isopropanolamines 1 and 2 were performed in comparison with diarylbutanols, a new class of non peptidic anti-PR agents, recently discovered by Agouron Pharmaceuticals. QSAR and CoMFA models based on 30 diarylbutanols used as a training set were developed. The obtained models were used to investigate the binding mode of the newly synthesized derivatives 1 and 2. The results of this study suggest that N-aryl heteroarylisopropanolamines bind to the PR active site similarly to the diarylbutanols of Agouron.

The synthesis, anti-Candida activity, and quantitative structure-activity relationship (QSAR) studies of a series of 2,4-dichlorobenzylimidazole derivatives having a phenylpyrrole moiety (related to the antibiotic pyrrolnitrin) in the alpha-position are reported. A number of substituents on the phenyl ring, ranging from hydrophobic (tert-butyl, phenyl, or 1-pyrrolyl moiety) to basic (NH(2)), polar (CF(3), CN, SCH(3), NO(2)), or hydrogen bond donors and acceptor (OH) groups, were chosen to better understand the interaction of these compounds with cytochrome P450 14-alpha-lanosterol demethylase (P450(14DM)). Finally, the triazole counterpart of one of the imidazole compounds was synthesized and tested to investigate influence of the heterocyclic ring on biological activity. The in vitro antifungal activities of the newly synthesized azoles 10p-v,x-c' were tested against Candida albicans and Candida spp. at pH 7.2 and pH 5.6. A CoMFA model, previously derived for a series of antifungal agents belonging to chemically diverse families related to bifonazole, was applied to the new products. Because the results produced by this approach were not encouraging, Catalyst software was chosen to perform a new 3D-QSAR study. Catalyst was preferred this time because of the possibility of considering each compound as a collection of energetically reasonable conformations and of considering alternative stereoisomers. The pharmacophore model developed by Catalyst, named HYPO1, showed good performances in predicting the biological activity data, although it did not exhibit an unequivocal preference for one enantiomeric series of inhibitors relative to the other. One aromatic nitrogen with a lone pair in the ring plane (mapped by all of the considered compounds) and three aromatic ring features were recognized to have pharmacophoric relevance, whereas neither hydrogen bond acceptor nor hydrophobic features were found. These findings confirmed that the key interaction of azole antifungals with the demethylase enzyme is the coordination bond to the iron ion of the porphyrin system, while interactions with amino acids localized in proximity of heme could modulate the biological activity of diverse antifungal agents. In conclusion, HYPO1 conveys important information in an intuitive manner and can provide predictive capability for evaluating new compounds.

A number of known antifungal pyrrole derivatives and some newly synthesized compounds (5-33) were tested in vitro against Mycobacterium tuberculosis CIP 103471. The majority of tested compounds were efficient antimycobacterial agents showing MIC values ranging from 0.5 to 32 microg/mL. A 3-D-QSAR study has been performed on these pyrrole derivatives to correlate their chemical structures with their observed inhibiting activity against M. tuberculosis. Due to the absence of information on a putative receptor responsible for this activity, classical quantitative structure-activity relationships (QSAR) and comparative molecular field analysis (CoMFA) have been applied. A model able to well correlate the antimycobacterial activity with the chemical structures of pyrrole derivatives 5-33 has been developed which is potentially helpful in the design of novel and more potent antituberculosis agents. The combination of CoMFA with classical QSAR descriptors led to a better hybrid 3-D-QSAR model, that successfully explains the structure-activity relationships (r2 = 0.86) of the training set. A comparison between the QSAR, CoMFA and mixed QSAR-CoMFA models is also presented. The hybrid model is to be preferred, however, because of its lowest values of the average absolute error of prediction toward a limited external test set.

Using 2,6-dichloro-4-aminopyrimidine, a number of uracil and cytosine derivatives with both arylthio and alkoxy moieties were prepared. These novel pyrimidines share chemical similarities with DABOs and HEPTs, two classes of non-nucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors (NNRTIs), which have been widely studied of late. All new derivatives were tested in MT-4 cells to explore their potential in vivo anti-HIV activity. Like other NNRTIs, they selectively inhibit HIV-1 but not HIV-2. The majority of test derivatives were found to have low potency and were sometimes more cytotoxic than zidovudine and emivirine (formerly MKC-442), used here as reference drugs. Uracil and cytosine derivatives bearing a sec-butoxy chain and a methyl-substituted benzenesulphonyl moiety were the most potent. Enzyme assays proved that these derivatives target RT. Structure-activity relationship studies established a correlation between the anti-HIV-1 activity and the meta substitution on the phenyl ring; furthermore, oxidation of sulphide to sulphone significantly increased the potency of certain derivatives.

During development of nitroheterocycles with potential antimycobacterial activities we have tested against Mycobacterium tuberculosis a number of pyrroles strictly related to pyrrolnitrin, an antifungal antibiotic isolated from Streptomyces pyrrocinia. Some of the tested arylpyrrole derivatives and pyrrolnitrin have shown appreciable inhibiting activity against M. tuberculosis and M. avium. SAR studies well correlate antimycobacterial potency with the presence of halogens in the phenyl ring and a nitro group at position 3 of pyrrole.

Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2, 4-dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1, 3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the cinnamoyl residue C=C-C=O in a syn disposition, differently from flavone derivatives characterized by an anti arrangement about the same fragment. Certain inhibitors, lacking one of the two pharmacophoric catechol hydroxyls, retain moderate potency thanks to nonpharmacophoric fragments (i.e., a m-methoxy group in curcumin) which favorably interact with an "accessory" region of IN. This region is supposed to be located adjacent to the binding site accommodating the pharmacophoric dihydroxycinnamoyl moiety. Disruption of coplanarity in the inhibitor structure abolishes activity owing to poor shape complementarity with the target or an exceedingly high strain energy of the coplanar conformation.

The synthesis of pyrrolo[2,1-d][1,2,5]benzothiadiazepin-7(6H)-one 5,5-dioxide has been achieved by reaction between 2-(1H-pyrrol-1-yl)benzenesulfonamide and triphosgene. N-Ethylation of the tricyclic derivative afforded 6-ethylpyrrolo[2,1-d][1,2,5] benzothiadiazepin-7(6H)-one 5,5-dioxide, also obtained by the action of trifosgene on N-ethyl 2-(1H-pyrrol-1-yl)benzenesulfonamide. Preparation of pyrrole derivatives from 2-aminobenzenesulfonamide and its N-ethyl derivative by Clauson-Kaas procedure required preliminary protection of the sulfonamide function.

A series of 56 azole antifungal agents belonging to chemically diverse families related to bifonazole, one of the antimycotic drugs of clinical use, were investigated using the comparative molecular field analysis (CoMFA) paradigm. The studied compounds, which have been already synthesized and reported to be active in vitro against Candida albicans, were divided into a training set and a test set. The training set consisted of 40 molecules from all the different structural classes. Due to the lack of experimental structural data on these derivatives, molecular mechanics techniques were used to obtain putative active conformations for all the compounds. the correctness of this molecular modeling work was confirmed a posteriori by comparison with structural data of the analog 2w obtained by X-ray crystallographic analysis (Massa, S.; et al. Eur. J. Med. Chem. 1992, 27, 495-502). Two different alignment rules of the training set molecules were used in this study and are based on the assumption that according to published results on azole antifungal agents, all the studied compounds exert their inhibitory activity through the coordination of their azole moiety to the protoporphyrin iron atom of the fungal lanosterol 14alpha-demethylase enzyme. The predictive ability of each resultant CoMFA model was evaluated using a test set consisting of 16 representative compounds that belong to all the different structural classes. The best 3D-quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r2 values equal to 0.57, 0.95, and 0.69, respectively. The average absolute error of predictions of this model is 0.30 log units, and the structural moieties of the studied antifungal agents which are thought to contribute to the biological activity were identified. The predictive capability of this model could be exploited in further synthetic studies on antifungal azoles. Furthermore, the results obtained by using two different alignments of the inhibitors suggest that the binding mode of these molecules involves both a coordination to the iron protoporphyrin atom and an additional, likewise relevant, hydrophobic interaction with the active site.

A new class of potent antifungal agents, namely, 3-aryl-4-[alpha-(1H-imidazol-1-yl)arylmethyl]-pyrroles, is described. These compounds are related to bifonazole and pyrrolnitrin, two compounds belonging to the class of antimycotic drugs. The synthesis of the title pyrroles has been performed starting from 1,3-diaryl-2-propen-1-ones, which were reacted with tosylmethyl isocyanide to give 3-aroyl-4-arylpyrroles. Reduction of the resulting compounds by lithium aluminum hydride furnished the related alcohols, which were treated with 1,1'-carbonyldimidazole to afford the required imidazole derivatives. Forty-four new pyrroles which incorporate an (arylmethyl)imidazole moiety in the 3-arylpyrrole structure were prepared by the above procedure and tested in vitro against Candida albicans and Candida spp. Among test compounds, 10 were found to be highly active against C. albicans. The most active derivative (27) was twice as potent (MIC90) as bifonazole, and its activity was 4 times greater than those of miconazole and ketoconazole. The other nine compounds showed antifungal activity of the same order of that of bifonazole and were ca. 2 times as active as miconazole and ketoconazole. Derivatives 21 and 27 tested in vivo against C. albicans A170 were shown to be highly effective in rabbit skin candidosis. Pharmacological studies on compounds 27 and other related pyrroles (19, 35, 36, 38, 39, and 49) are in progress to select one of them as a potential candidate for clinical experiments.

Various bipyrryl analogues of bifonazole were synthesized starting from aryl-3-pyrryl-1-imidazolylmethanes. The introduction of a second pyrryl portion was performed by linking an acrylate moiety at 1-position of the pyrrole ring and then by treatment with TosMIC. The bipyrryl esters were hydrolyzed and decarboxylated to afford the required imidazoles. All new imidazole derivatives were tested against Candida albicans and Candida spp using as standard controls miconazole, bifonazole and ketoconazole.

The in vitro antifungal activities of some naphthyl and thienyl derivatives of 1H-imidazol-1-yl-4-phenyl-1H-pyrrol-3-ylmethane against Candida albicans and Candida spp are reported. The title derivatives were prepared starting from proper arylstirylketones, which were reacted with tosylmethylisocyanide (Tos-MIC) to afford the related 4-phenyl-1H-pyrrol-3-yl aryl ketones. Reduction of ketones to the corresponding carbinols followed by treatment of the last compounds with 1,1'-carbonyldiimidazole (CDI) gave the title imidazoles. The related N-methylpyrrole derivatives are also described.

The synthesis of various pyrrylphenylethanones resembling cathinone and lefetamine is described starting from 2-chloro-1-(1-methyl-1H-pyrrol-2-yl)-2-phenylethan-1-one. Some derivatives showed good antinociceptic activity, comparable to that of morphine. The neuropsychopharmacological profile of title compounds has been also studied to explore their action on C.N.S.