Efficient synthesis of coumarin-chalcones hybrids as new scaffold with antibacterial interest

The 14th International Electronic Conference on Synthetic Organic Chemistry session Natural Products ChemistryDue to the potential antibacterial activity of the chalcone and coumarin moieties, hybrid compounds containing both structures have been synthesized in good yield using the Knoevenagel reaction as the key stepSVR is grateful to the Spanish Ministry de Education and Science for the grant AP2008-04263. Our groups is grateful to We are grateful to the Spanish Ministry of Health and Consum (PS09/00501) and to Xunta da Galicia (CSA030203PR

Coumarin-Chalcone Hybrids as new scaffolds in drug discovery

The 13th International Electronic Conference on Synthetic Organic Chemistry session General Organic SynthesisThe first hydroxilated series of coumarin-chalcone derivatives has been synthesize starting from the corresponding salicyl aldehyde and β-ketoester precursors by a Knoevenagel reaction in order to obtain the methoxy derivatives which have been further hydrolyzed with a Lewis aci

Oxidation-labile linkers for controlled drug delivery

The continuous symbiosis throughout chemical biology and drug discovery has led to the design of innovative bifunctional molecules for targeted and controlled drug delivery. Among the different tools, protein-drug and peptide-drug conjugates are trend approaches to achieve targeted delivery, selectivity and efficacy. To meet the main goals of these bioconjugates, the selection of the appropriate payloads and linkers is crucial, as they must provide in vivo stability, while they may also help to achieve the therapeutic target and action. In neurodegenerative diseases or some cancer types, where oxidative stress plays an important role, linkers sensitive to oxidative conditions may be able to release the drug once the conjugate achieves the target. Considering specially this specific application, this mini-review covers the most relevant publications on oxidation-labile linkersM.J.M. thanks Ministerio de Ciencia e Innovación (PID2020-116076RJ-I00/AEI/10.13039/501100011033) for the financial support. A.C. thanks FCT for the PhD grant (2021.05149.BD)S

QSAR & Network-based multi-species activity models for antifungals

The 11th International Electronic Conference on Synthetic Organic Chemistry session Computational ChemistryThere are many pathogen microbial species with very different antimicrobial drugs susceptibility. In this work, we selected pairs of antifungal drugs with similar/dissimilar species predicted-activity profile and represented it as a large network, which may be used to identify drugs with similar mechanism of action. Computational chemistry prediction of the biological activity based on quantitative structure-activity relationships (QSAR) susbtantialy increases the potentialities of this kind of networks avoiding time and resources consming experiments. Unfortunately, almost QSAR models are unspecific or predict activity against only one species. To solve this problem we developed here a multi-species QSAR classification model, which outputs were the inputs of the above-mentioned network. Overall model classification accuracy was 87.0% (161/185 compounds) in training, 83.4% (50/61) in validation, and 83.7% for 288 additional antifungal compounds used to extent model validation for network construction. The network predicted has 59 nodes (compounds), 648 edges (pairs of compounds with similar activity), low coverage density d = 37.8%, and distribution more close to normal than to exponential. These results are more characteristic of a not-overestimated random network, clustering different drug mechanisms of actions, than of a less useful power-law network with few mechanisms (network hubs)Gonzalez-Díaz H. acknowledges contract/grant sponsorship from the Program Isidro Parga Pondal of the “Dirección Xeral de Investigación y Desenvolvemento” of “Xunta de Galicia”. This author also acknowledges two contracts as guest professor in the Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Spain in 2006. The authors thank the Xunta de Galicia (projects PXIB20304PR and BTF20302PR) and the Ministerio de Sanidad y Consumo (project PI061457) for partial financial suppor

Unify QSAR approach to antibacterial activity of organic drugs against different species

The 10th International Electronic Conference on Synthetic Organic Chemistry session Bioorganic Chemistry and Natural ProductsThere are many different kinds of pathogen bacteria species with very different susceptibility profile to different antibacterial drugs. One limitation of QSAR models are the biological activity of drugs against only one bacteria species. In previous paper we develop one unified Markov model to describe the biological activity of different drugs tested in the literature against some of the antimicrobial species. Consequently predicting the probability with which a drug is active against different bacteria species with a single unify model is a goal of the major importance. This work develops one unified Markov model to describe the biological activity of more than 70 drugs tested in the references against to 96 bacteria species. Linear Discriminant Analysis (LDA) classifying drugs as active or non-active against the different tested bacteria species processed the data. The model correctly classifies 199 out of 237 active compounds (83.9%) and 168 out of 200 non-active compounds (84%). Overall training predictability was 84% (367 out of 437 cases). Validation of the model was carring out by means of external predicting series, classifying the model 202 out 243, 83.13% of compounds. In order to show how the model function in practice a virtual screening was carring out recognizing the model as active 84.5%, 480 out of 568 antibacterial compounds not used in training or predicting series. The present is an attempt to calculate withing a unify framework probabilities of antibacterial action of drugs against many different speciesAuthors thank projects PXIB20304PR and BTF20302PR from Xunta de Galiza for partial financial suppor

Detection of drug-drug interactions by modeling interaction profile fingerprints

Drug-drug interactions (DDIs) constitute an important problem in postmarketing pharmacovigilance and in the development of new drugs. The effectiveness or toxicity of a medication could be affected by the co-administration of other drugs that share pharmacokinetic or pharmacodynamic pathways. For this reason, a great effort is being made to develop new methodologies to detect and assess DDIs. In this article, we present a novel method based on drug interaction profile fingerprints (IPFs) with successful application to DDI detection. IPFs were generated based on the DrugBank database, which provided 9,454 well-established DDIs as a primary source of interaction data. The model uses IPFs to measure the similarity of pairs of drugs and generates new putative DDIs from the non-intersecting interactions of a pair. We described as part of our analysis the pharmacological and biological effects associated with the putative interactions; for example, the interaction between haloperidol and dicyclomine can cause increased risk of psychosis and tardive dyskinesia. First, we evaluated the method through hold-out validation and then by using four independent test sets that did not overlap with DrugBank. Precision for the test sets ranged from 0.4–0.5 with more than two fold enrichment factor enhancement. In conclusion, we demonstrated the usefulness of the method in pharmacovigilance as a DDI predictor, and created a dataset of potential DDIs, highlighting the etiology or pharmacological effect of the DDI, and providing an exploratory tool to facilitate decision support in DDI detection and patient safety.This work was supported by grants R01 LM010016 (CF), R01 LM010016-0S1 (CF), R01 LM010016-0S2 (CF), R01 LM008635 (CF), “Plan Galego de Investigación, Innovación e Crece-mento 2011–2015 (I2C)”, European Social Fund (ESF) and Angeles Alvariño program from Xunta de Galicia (Spain)S

QSAR for Anti-RNA-Virus Activity, Synthesis, and Assay of Anti-RSV Carbonucleosides Given an Unify Representation of Spectraö Moments, Quadratic, and Topologic Indices

The 9th International Electronic Conference on Synthetic Organic Chemistry session Computational ChemistryThe unify representation of spectral moments, classic topologic indices, quadratic indices, and stochastic molecular descriptors shown that all these molecular descriptors lie within the same family. Consequently, the same priori probability for a success quantitative-structure-activity-relationship (QSAR) may be expected no matter which indices are selected. Herein, we used stochastic spectral moments as molecular descriptors to seek a QSAR using a database of 221 bioactive compounds previously tested against diverse RNA-viruses and 402 non-active ones. The QSAR model thus obtained correctly classifies 90.9 % of compounds in training. The model also correctly classifies a total of 87.9 % of 207 compounds on additional external predicting series, 73 of them having anti-RNA-virus activity and 134 non-active ones. In addition, all compounds were regrouped into five different subsets for leave-group-out studies: 1) antiinfluenza, 2) anti-picornavirus, 3) anti-paramyxovirus, 4) anti-RSV/anti-influenza, and 5) broad range anti-RNA-virus activity. The model has retained overall accuracies about 90 % on these studies validating model robustness. Finally, we exemplify the practical use of the model with the discovery of compounds 124 and 128. These compounds presented MIC50 values = 3.2 and 8 µg/mL against respiratory syncytial virus (RSV) respectively. Both compounds have also low cytotoxicity expressed by their Minimal Cytotoxic Concetrations > 400 µg/mL for HeLa cells. The present approach represent and effort toward a formalization and application of molecular indices in bioinformatics, bioorganic and medicinal chemistryAuthors would like to express their gratitude by partial financial support to the Department of Organic Chemistry, University of Santiago de Compostel

Synthesis of new phthalazinedione derivatives

The 15th International Electronic Conference on Synthetic Organic Chemistry session General Organic SynthesisIn the past few decades, the synthesis of new heterocyclic compounds has been a subject of great interest due to their wide applicability. Among a large variety of heterocyclic compounds, heterocycles containing phthalazine moiety were reported to possess anticonvulsant, cardiotonic, and vasorelaxant activities. Therefore, a number of methods have been reported for the synthesis of phthalazine derivatives. Despite the available methods, the development of new synthetic methods for the efficient preparation of heterocycles containing phthalazine ring fragment is therefore an interesting challenge. With these precedents and with the aim of preparing new derivatives with potential pharmacological activity, we have synthesized new phthalazinedione derivatives by introducing halogenoalkyl substituents in one of the NH-nucleophilic groups. So, we started with 4-chloro-phthalic anhydride, which reacted with methyl- hydrazine, in MW mild conditions. After purification, we obtained two different isomers of phthalizediones, 8-chloro-2-methyl-2, 3-dihydro-phthalazine-1, 4-dione and 8-chloro-3-methyl-2, 3-dihydro-phthalazine-1,4-dione. Then halogenoalkyl substituents with different chain length were introduced in the nitrogen group in a very efficient way. Finally halogen atom of alkyl chains was replaced by an azide group. The described synthetic route will allow us to condense a nitrogen heterocyclic ring on the phatalazinone moiety and obtain a new tricyclic scaffold with promising pharmacological propertie

Trending Topics on Coumarin and Its Derivatives in 2020

Coumarins are naturally occurring molecules with a versatile range of activities. Their structural and physicochemical characteristics make them a privileged scaffold in medicinal chemistry and chemical biology. Many research articles and reviews compile information on this important family of compounds. In this overview, the most recent research papers and reviews from 2020 are organized and analyzed, and a discussion on these data is included. Multiple electronic databases were scanned, including SciFinder, Mendeley, and PubMed, the latter being the main source of information. Particular attention was paid to the potential of coumarins as an important scaffold in drug design, as well as fluorescent probes for decaging of prodrugs, metal detection, and diagnostic purposes. Herein we do an analysis of the trending topics related to coumarin and its derivatives in the broad field of drug discoveryThis research was funded by Xunta de Galicia (Galician Plan of Research, Innovation and Growth 2011–2015, Plan I2C, ED481B 2014/027-0, ED481B 2014/086–0 and ED481B 2018/007) and Fundação para a Ciência e Tecnologia (FCT, CEECIND/02423/2018 and UIDB/00081/2020)S

Synthesis of new possible monoamine oxidase inhibitors

The 14th International Electronic Conference on Synthetic Organic Chemistry session Natural Products ChemistryWe have generated different resveratrol-coumarin hybrids with the aim of evaluate their biological applications and their pharmacological properties, particularly the inhibitory activity of monoamine oxidase enzyme. According to that, a first series of 3-aryl-4-hydroxycoumarins has been synthesized starting from aryl boronic acids and phenyliodonium zwitterions precursors by a palladium-catalyzed coupling reactionWe are grateful to the Spanish Ministerio de Sanidad y Consumo (PS09/00501) and to Xunta da Galicia (CSA030203PR). Silvia Serra is grateful to Programma Master and Back PR_MAB‐ A2009‐613 Regione Sardegn