Letteratura scientifica selezionata sul tema "Minimal pharmacophores"

Pharmacophore models are an accurate and minimal tridimensional abstraction of intermolecular interactions between chemical structures, usually derived from a group of molecules or from a ligand-target complex. Only a limited amount of solutions exists to model comprehensive pharmacophores using the information of a particular target structure without knowledge of any binding ligand. In this work, an automated and customable tool for truly target-focused (T²F) pharmacophore modeling is introduced. Key molecular interaction fields of a macromolecular structure are calculated using the AutoGRID energy functions. The most relevant points are selected by a newly developed filtering cascade and clustered to pharmacophore features with a density-based algorithm. Using five different protein classes, the ability of this method to identify essential pharmacophore features was compared to structure-based pharmacophores derived from ligand-target interactions. This method represents an extremely valuable instrument for drug design in a situation of scarce ligand information available, but also in the case of underexplored therapeutic targets, as well as to investigate protein allosteric pockets and protein-protein interactions.

Until the 20th century fungal infections were rather easy cured, and the need of new antifungal drugs was low. However, low choice of antifungal preparations, their toxicity, limited spectrum of action, and ability to produce resistant strains show the need of new effective medicines for systemic fungal diseases in nowadays. Our goal of research was to synthesize new antimicrobial compounds containing three or more pharmacophores in one molecule. The initial 5-substituted-2-methylmercaptothiazolidin-4-ones were subjected to S-demethylation to yield 2- amino-substituted thiazolidinones. Ethacridine, nitrofuran aldehydes and nitrobenzene aldehyde as pharmacophoric amino or aldehyde group having compounds have been used. Antimicrobial (antifungal) activity of the new compounds was screened in vitro in these bacterial cultures: Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Bacillus subtilis ATCC 6633, Klebsiella pneumoniae ATCC 33499 and fungal cultures: Candida albicans ATCC 60l93, Candida glabrata, Candida krusei, Candida kefyr ATCC 86l4, Candida tropicalis ATCC 8302, Candida parapsilosis. Results showed that the new compounds were significantly more effective as antimicrobial agents than initial preparation ethacridine. Ethacridine derivatives were not only effective against numerous gram-positive and some gram-negative bacteria, but the spectrum of action has been discovered against fungi. Minimal fungistatic concentration varies in the range l0.0–750 µg/mL and antibacterial concentration is in the range 62.5–l000 µg/mL. Compound 2a having nitrofuryl substituent in the fifth position of tiazolidine cycle was the most active of synthesized ethacridine compounds. The obtained results gave the opportunity to separate the perspective group of potential antiinfective compounds.

The problem of lung damage originating from excessive inflammation and cytokine release during various types of infections remains relevant and stimulates the search for highly effective and safe drugs. The biological activity of the latter may be associated with the regulation of hyperactivation of certain immune cells and enzymes. Here, we propose the design and synthesis of amino derivatives of 4,6- and 5,7-diaryl substituted pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines as promising double-acting pharmacophores inhibiting IL-6 and NO. The anti-inflammatory activity of 14 target compounds was studied on isolated primary murine macrophages after LPS stimulation. Seven compounds were identified to inhibit the synthesis of nitric oxide and interleukin 6 at a concentration of 100 µM. The most active compounds are micromolar inhibitors of IL-6 secretion and NO synthesis, showing a minimal impact on innate immunity, unlike the reference drug dexamethasone, along with acceptable cytotoxicity. Evaluation in an animal model of acute lung injury proved the protective activity of compound 6e, which was supported by biochemical, cytological and morphological markers.

ABSTRACT Curcumin is a biologically active phytochemical which manifests therapeutic activities in numerous health conditions, including cancer. Several curcuminoids obtained naturally and synthesized artificially also showcase anti-cancer and anti-tumorigenic effects. However, its water insolubility poses difficulties in its application to biological systems, lowering its availability in living tissues, which can be overcome by using various micro-encapsulation and nano-formulations of curcumin. When used in combination with other chemotherapeutic drugs, curcumin enhances the anti-carcinogen potential and reduces the side effects induced via chemotherapy. Structural modelling of basic pharmacophores of curcumin can enhance its biological and pharmacokinetic properties, as revealed by structure-activity relationship studies of curcumin. Various clinical trials of curcumin have proven its worth as an anti-neoplastic agent in humans, with minimal side effects. Its mechanism of action involves blockage of cell-signalling pathways and cellular enzymes, promotion of immunomodulatory effects and induction of programmed cell death in cancerous cells. Curcumin is an interesting molecule with diverse effects on various diseases, but its absolute potential has yet to be reached. Hence, more in-depth studies and clinical trials are needed. This review outlines curcumin’s chemical properties and summarizes its anti-cancer and pharmacokinetic potential.

Chronic pain is a major medical issue which reduces the quality of life of millions and inflicts a significant burden on health authorities worldwide. Currently, management of chronic pain includes first-line pharmacological therapies that are inadequately effective, as in just a portion of patients pain relief is obtained. Furthermore, most analgesics in use produce severe or intolerable adverse effects that impose dose restrictions and reduce compliance. As the majority of analgesic agents act on the central nervous system (CNS), it is possible that blocking pain at its source by targeting nociceptors would prove more efficient with minimal CNS-related side effects. The development of such analgesics requires the identification of appropriate molecular targets and thorough understanding of their structural and functional features. To this end, plant and animal toxins can be employed as they affect ion channels with high potency and selectivity. Moreover, elucidation of the toxin-bound ion channel structure could generate pharmacophores for rational drug design while favorable safety and analgesic profiles could highlight toxins as leads or even as valuable therapeutic compounds themselves. Here, we discuss the use of plant and animal toxins in the characterization of peripherally expressed ion channels which are implicated in pain.

Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new and effective anti-cancer agents. As both chalcones and 1,2,3-triazoles are valuable pharmacophores/privileged structures in the search for anticancer compounds, in this work, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against oral squamous cell carcinoma. By using different in silico, in vitro, and in vivo approaches, we demonstrated that compound 1f has great cytotoxicity and selectivity against OSCC (higher than carboplatin and doxorubicin) and other cancer cells in addition to showing minimal toxicity in mice. Furthermore, we demonstrate that induced cell death occurs by apoptosis and cell cycle arrest at the G2/M phase. Moreover, we found that 1f has a potential affinity for MDM2 protein, similar to the known ligand nutlin-3, and presents a better selectivity, pharmacological profile, and potential to be orally absorbed and is not a substrate of Pg-P when compared to nutlin-3. Therefore, we conclude that 1f is a good lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers.

Macrocyclic imine phycotoxins are an emerging class of chemical compounds associated with harmful algal blooms and shellfish toxicity. Earlier binding and electrophysiology experiments on nAChR subtypes and their soluble AChBP surrogates evidenced common trends for substantial antagonism, binding affinities, and receptor-subtype selectivity. Earlier, complementary crystal structures of AChBP complexes showed that common determinants within the binding nest at each subunit interface confer high-affinity toxin binding, while distinctive determinants from the flexible loop C, and either capping the nest or extending toward peripheral subsites, dictate broad versus narrow receptor subtype selectivity. From these data, small spiroimine enantiomers mimicking the functional core motif of phycotoxins were chemically synthesized and characterized. Voltage-clamp analyses involving three nAChR subtypes revealed preserved antagonism for both enantiomers, despite lower subtype specificity and binding affinities associated with faster reversibility compared with their macrocyclic relatives. Binding and structural analyses involving two AChBPs pointed to modest affinities and positional variability of the spiroimines, along with a range of AChBP loop-C conformations denoting a prevalence of antagonistic properties. These data highlight the major contribution of the spiroimine core to binding within the nAChR nest and confirm the need for an extended interaction network as established by the macrocyclic toxins to define high affinities and marked subtype specificity. This study identifies a minimal set of functional pharmacophores and binding determinants as templates for designing new antagonists targeting disease-associated nAChR subtypes.

Abstract Many patients with B-cell lymphomas, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL), are not cured by conventional chemo-immunotherapy. One reason for this is because these drugs, while effective, are limited by their narrow therapeutic window and significant toxicities. B-cell lymphomas are highly dependent on DNA damage checkpoints, and hence are biologically responsive to drugs that trigger these checkpoints. Hence, In order to identify superior DNA damaging anti-lymphoma drugs we evaluated a series of novel, third generation, DNA-directed alkylating agents that have DNA specific binding domains chemically linked via urea, carbamate or hydrazinecarboxamide to N-mustard pharmacophores. The chemically favorable water-soluble ureidomustine (BO-1055) was evaluated for activity against 23 human lymphoma cell lines including MCL, DLBCL (GCB and ABC subtype) and a spontaneous murine B-cell lymphoma. Fifty % of these MCL and DLBCL cell lines exhibited BO-1055 IC50 values in the nanomolar range including even markedly chemo-resistant cell lines as OCI-Ly10 (IC50 0.117μM ±0.21). In marked contrast, against normal human tissues (lung fibroblast IMR90, kidney fibroblast CV1, mesenchymal stromal, bronchial epithelium, myofibroblast, bone marrow-derived endothelium) and hematopoietic cells (cord blood CD34+ cells, colony-forming assay for hematopoietic progenitors) and in cobblestone area-forming assay for hematopoietic stem cells, BO-1055 IC50s were > 10μM. Hence BO-1055 has a significant therapeutic window (50-100-fold) between its toxicity against B-cell lymphomas compared to normal human cells. We evaluated BO-1055 cardiotoxicity in the HL-1 cardiomyocyte line and observed a 227-fold less cytotoxicity compared to Doxorubicin. Drug combination studies with BO-1055 and an Hsp90 inhibitor (PU-H71), an Hsp70 inhibitor (TT46), doxorubicin and bortezomib (Velcade) demonstrated synergistic effects based on Compusyn analysis with very low combination indices in 50% of lymphoma cell lines. The synergistic effect was not observed in normal cells. Notably, BO-1055 caused downregulation of the critical lymphoma oncoproteins MYC and BCL6, but not Bcl2. BCL6 normally suppresses the ATR-driven S-phase checkpoint. Accordingly treatment with BO-1055 resulted in accumulation of cells in S-phase and up-regulation of proteins involved in DNA repair and intra-S-phase checkpoints [MRE11, p-P95/NBS1 (ser343), RAD50, p-ATR (ser428)]. Finally, xenograft experiments in NSG mice bearing MCL JEKO1 GFP/luciferase+ tumors treated with BO-1055 (30mg/kg) 3x/week showed complete tumor remission after 2 weeks of treatment as monitored by luminescent imaging. In summary, BO-1055 is emerging as a potent therapeutic agent for B-cell lymphomas, with little toxicity against normal tissues and hence potentially wider therapeutic window than current lymphoma drugs. Disclosures Caldas Lopes: BOtique Biopharm: Employment.

Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.

ABSTRACT We present data from antimicrobial assays performed in vitro that pertain to the potential clinical utility of a novel rifamycin-quinolone hybrid antibiotic, CBR-2092, for the treatment of infections mediated by gram-positive cocci. The MIC90s for CBR-2092 against 300 clinical isolates of staphylococci and streptococci ranged from 0.008 to 0.5 μg/ml. Against Staphylococcus aureus, CBR-2092 exhibited prolonged postantibiotic effects (PAEs) and sub-MIC effects (SMEs), with values of 3.2, 6.5, and >8.5 h determined for the PAE (3× MIC), SME (0.12× MIC), and PAE-SME (3× MIC/0.12× MIC) periods, respectively. Studies of genetically defined mutants of S. aureus indicate that CBR-2092 is not a substrate for the NorA or MepA efflux pumps. In minimal bactericidal concentration and time-kill studies, CBR-2092 exhibited bactericidal activity against staphylococci that was retained against rifampin- or intermediate quinolone-resistant strains, with apparent paradoxical cidal characteristics against rifampin-resistant strains. In spontaneous resistance studies, CBR-2092 exhibited activity consistent with balanced contributions from its composite pharmacophores, with a mutant prevention concentration of 0.12 μg/ml and a resistance frequency of <10−12 determined at 1 μg/ml in agar for S. aureus. Similarly, CBR-2092 suppressed the emergence of preexisting rifamycin resistance in time-kill studies undertaken at a high cell density. In studies of the intracellular killing of S. aureus, CBR-2092 exhibited prolonged bactericidal activity that was superior to the activities of moxifloxacin, rifampin, and a cocktail of moxifloxacin and rifampin. Overall, CBR-2092 exhibited promising activity in a range of antimicrobial assays performed in vitro that pertain to properties relevant to the effective treatment of serious infections mediated by gram-positive cocci.

Les polycétides d’origine bactérienne sont une source importante de molécules anti-infectieuses et anticancéreuses d’origine naturelle utilisées en thérapie. Cependant, leurs structures doivent souvent être optimisées afin d'améliorer leurs propriétés thérapeutiques. Les stambomycines, une famille de macrolides parmi les plus grands polycétides connus (elles possèdent un noyau macrolactone à 51 membres), ont été récemment découvertes par une approche de genome mining chez la bactérie Streptomyces ambofaciens ATCC23877. Ces molécules présentent une activité anticancéreuse prometteuse. Six formes de stambomycines ont été caractérisées. Elles diffèrent les unes des autres par la fonctionnalité alkyle au niveau de la position C-26 du noyau macrolactone. Cette variabilité est due au choix alternatif d’unités d'extension par un domaine acyltransférase exceptionnel, le domaine AT12, de la polycétide synthase modulaire (PKS) responsable de la synthèse des stambomycines. Étant donné la taille importante du cycle lactone et la promiscuité intrinsèque du domaine AT12, il existe un intérêt substantiel à accéder à des dérivés stambomycines par réduction de la taille du noyau ou par substitution de la chaine latérale en C-26. Ces dérivés pourraient conserver la bioactivité des structures parentales ou présenter des propriétés améliorées voire nouvelles. Dans ce travail, nous avons mis à profit notre compréhension actuelle des systèmes de PKS modulaires pour raccourcir en interne la chaîne de production de stambomycines, ce qui a permis de générer avec succès, bien qu'à faible rendement, des dérivés avec un noyau macrolactone de taille réduite (des "mini-stambomycines" présentant un noyau à 37 membres). Grâce à une analyse minutieuse, nous avons pu identifier les multiples facteurs expliquant les faibles rendements, ce qui permettra d’éclairer les futures stratégies d'ingénierie. En outre, grâce à une stratégie de mutasynthèse, nous avons pu exploiter la large spécificité du domaine AT12 pour générer six nouveaux analogues de stambomycine présentant différentes substitutions en position C-26. Enfin, nous avons identifié de manière tout à fait inattendue trois classes de sidérophores étroitement apparentées aux desferrioxamines produites par S. ambofaciens. Un certain nombre des métabolites clés générés pendant ce travail constitue une source de nouvelles biomolécules avec des applications thérapeutiques potentielles. Les prochaines étapes consisteront à purifier ces composés, à déterminer leur structure puis à évaluer leurs activités biologiques
The polyketide secondary metabolites of bacteria are a rich source of bioactive agents, with notable applications in anti-infective and anti-cancer therapy. However, their structures often need to be optimized in order to tailor their therapeutic and biophysical properties. The 51-membered macrolide stambomycins, among the largest of known polyketides, were recently discovered by genome mining in Streptomyces ambofaciens ATCC23877, and notably exhibit promising anti-cancer activity. The family encompasses six members which differ from each other in the alkyl functionality at C-26, due to the alternative choice of extender units by an exceptional acyl transferase domain (AT12) of the modular polyketide synthase (PKS) responsible for synthesizing the stambomycin core. Given their enormous size of the stambomycins and the intrinsic promiscuity of AT12, there is substantial interest in accessing ring-contracted and C-26 substituted derivatives of this compounds which might retain the bioactivity of the parental structures, or exhibit improved or even new properties. In this work, we have leveraged our current understanding of modular PKS systems to internally contract the stambomycin assembly line, leading to the successful generation, albeit at low yield, of target smaller derivatives (37-membered ‘mini-stambomycins’). By careful analysis, we could identify multiple factors contributing to the low titers, information which should inform future engineering strategies. Furthermore, using a mutasynthesis strategy, we were able to exploit the broad specificity of the AT12 domain to create 6 novel C-26 substituted stambomycin analogues. Finally, we unexpectedly identified three series of novel desferrioxamine siderophores produced by S. ambofaciens. As a number of key metabolites generated in this work have potential interest for therapeutic applications, they will be targeted for purification, structural characterization and biological evaluation