Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors

In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common component of these regimens. Food and Drug Administration (FDA)- approved NS5A inhibitors, although very potent, do not have the same potency against all eight genotypes of HCV. Therefore, this study aims to synthesize NS5A inhibitor analogues with high potency pan-genotypic activity and high metabolic stability. Starting from an NS5A inhibitor scaffold previously identified by our research group, we made several modifications. Two series of compounds were created to test the effect of changing the length and spatial conformation (para-para vs. meta-metapositioned bis-imidazole-proline-carbamate), replacing amide groups in the linker with imidazole groups, as well as different end-cap compositions and sizes. The frontrunner inhibits genotype 1b (Con1) replicon, with an EC50 value in the picomolar range, and showed high genotypic coverage with nanomolar range EC50 values against four more genotypes. This together with its high metabolic stability (t1 ⁄2 > 120 min) makes it a potential preclinical candidate

Boronic Acid Group: A Cumbersome False Negative Case in the Process of Drug Design

Herein we present, an exhaustive docking analysis considering the case of autotaxin (ATX). HA155, a small molecule inhibitor of ATX, is co-crystallized. In order to further extract conclusions on the nature of the bond formed between the ligands and the amino acid residues of the active site, density functional theory (DFT) calculations were undertaken. However, docking does not provide reproducible results when screening boronic acid derivatives and their binding orientations to protein drug targets. Based on natural bond orbital (NBO) calculations, the formed bond between Ser/Thr residues is characterized more accurately as a polar covalent bond instead of a simple nonpolar covalent one. The presented results are acceptable and could be used in screening as an active negative filter for boron compounds. The hydroxyl groups of amino acids are bonded with the inhibitor’s boron atom, converting its hybridization to sp3

Design, synthesis and pharmacochenical evaluation of novel hybrid derivatives with possible biological activity

Nowadays the research of pleiotropic hybrid molecules is flourishing. Hybridmolecules are products of rational design bearing two or more pharmacophoremoieties in a single molecule, presenting a unique interest on the treatment ofcomplex diseases replacing common therapeutic approaches which include thesimultaneously usage of several drugs.In this dissertation we dealt with two distinct classes of hybrid multifunctionalmolecules. The design of these molecules whom was based on the most recentliterature data and the crystallographic data of the enzymes LOX, COX-2, Trypsin,ATX, PDE-2, DNA GyrB, topoIV ParE taken from the PDB.The first group includes hybrid derivatives of babrituric/thiobarbituric acid.The pyrimidine-2,4,6(1H,3H,5H)-trione and 2-thioxo-dihydropyrimidine4,6(1H,5H)-dionewere combined with various biologically active moieties through aKnoevenagel condensation. The products compiled a novel library that was subjectedto docking simulations over the protein X-ray data (LOX, COX-2, trypsin, ATX andPDE-2). Molecules that showed a multifunctional profile have been chosen to bechemically synthesized and biologically studied over the selected biological targets. The second group is consisted by hybrid molecules, analogues of the alkaloidOroidin, which is known for its antibacterial activity against Gram (+) bacteria.Computer aided drug design techniques were applied which in combination withLBDD and SBDD pointed to the more suitable derivatives, bearing differentpharmacophores linked via a peptide bond and an unsaturated chain, introducing theoroidin flexible aminoimidazole ending replacement by rigidified heterocyclic ringsthat maintained the free amine. The compiled library of molecules was screened fortheir binding over the E. coli DNA GyrB crystal data. The structures with the lowestscoring function were selected to be synthesized.The synthesis of the novel compounds was based on the implementation ofknown and modified procedures and techniques in an attempt to have efficient yields.All the compounds were purified through various techniques and identified bycontemporary spectrometric analysis.Through this study, the physicochemical properties (molar volume,stereochemistry) that are significant and optimum for the biological activities of thenovel hybrids, were found. The derivatives were studied in vitro over all the selectedbiological targets. Their antioxidant activities were determined as well.The biological results confirm that compounds TH35, TH19, TH31, TH36 andLJ39 are pleiotropic hybrid derivatives. Especially, compound TH35 constitutes apotent inhibitor for the enzymes LOX, COX-2 and PDE-2.Compounds TH19 and TH31 were found to be potent inhibitors of trypsin, COX-2, ATX, whereas compound TH36 exhibited a potent inhibitory activity ofCOX-2 with satisfactory neuroprotection over the HT22 cell line. Their antioxidantproperties explain in part their inhibitory activity over LOX and COX-2.Analogues of oroidin of the series LJ, were studied for their bacterial inhibitionon E. coli and S. aureus strains of DNA gyrase and Topo IV. LJ39 presents an exceptional interest as pleiotropic molecule (potent inhibitor of COX-2) whilecompound LJ24 strongly inhibits trypsin.Hybrid molecule TH18 resulted to a 24h tolerance of pain induced by a heatstimuli.Compounds TH18, TH19 and TH16 through their physicochemical propertiesare presenting the best "druglikeness profile".Τα τελευταία χρόνια η φιλοσοφία και η έρευνα πλειοτρόπων υβριδικών μορίων βρίσκεται σε άνθιση. Τα υβριδικά μόρια αποτελούν προϊόντα ορθολογικού σχεδιασμού και προκύπτουν από τον συνδυασμό δύο ή περισσοτέρων φαρμακοφόρων ομάδων σε ένα μόριο και παρουσιάζουν ιδιαίτερο ενδιαφέρον στην θεραπεία ασθενειών με πολύπλοκη αιτιολογία, στις οποίες η θεραπευτική προσέγγιση περιλαμβάνει συνήθως συνδυασμό φαρμάκων.Στην παρούσα διατριβή ασχοληθήκαμε με δύο κατηγορίες υβριδικών πολυδραστικών μορίων, ο σχεδιασμός των οποίων βασίστηκε: στα πιο πρόσφατα βιβλιογραφικά δεδομένα, καθώς επίσης και στα κρυσταλλογραφικά δεδομένα των ενζύμων LOX, COX-2, θρυψίνης, ATX, PDE-2, DNA GyrB, topoIV ParE που ανακτήθηκαν από την τράπεζα δεδομένων πρωτεϊνών.Την πρώτη ομάδα αποτελούν τα υβριδικά παράγωγα του βαρβιτουρικού/θειοβαρβιτουρικού οξέος. Οι πυριμιδινο-2,4,6(1H,3H,5H)-τριόνες καιοι 2-θειοξο-διυδροπυριμιδινο-4,6(1H,5H)-διόνες συνδυάστηκαν, ως συμπυκνωμέναKnoevenagel παράγωγα, με διάφορες γνωστές δραστικές αντιοξειδωτικές/αντιφλεγμονώδεις ομάδες και δημιουργήθηκε μια πρωτότυπη βιβλιοθήκη που δοκιμάσθηκε για την πρόσδεση των μορίων με τα κρυσταλλογραφικά δεδομένα των πρωτεϊνών (LOX, COX-2, θρυψίνη, ATX και PDE-2). Πολυδραστικά μόρια επιλέχθηκαν για να συντεθούν και μελετήθηκαν βιολογικά στους επιλεγμένους βιολογικούς στόχους.Την δεύτερη ομάδα υβριδικών μορίων αποτελούν ανάλογα της οροϊδίνης ενός αλκαλοειδούς με αντιβακτηριδιακή δράση κατά των Gram (+) βακτηρίων.Εφαρμόσθηκαν CADD τεχνικές με συνδυασμό των LBDD και SBDD με την βοήθεια των οποίων επιλέχθηκαν οι κατάλληλες ενώσεις που συνδυάζουν διάφορες φαρμακοφόρες ομάδες συνδεδεμένες μεταξύ τους μέσω μιας αμιδικής ακόρεστης αλυσίδας, εισάγοντας δύσκαμπτους ετεροκυκλικούς δακτυλίους που διατηρούν την αμινομάδα ελεύθερη προς αντικατάσταση του μητρικού ευλύγιστου αμινοϊμιδαζολικού άκρου του μορίου της οροϊδίνης, δημιουργώντας μια βιβλιοθήκη μορίων που δοκιμάσθηκε για την πρόσδεση με τα κρυσταλλογραφικά δεδομένα της πρωτεΐνης E. coli DNA GyrB. Επιλέχθηκαν να συντεθούν και να μελετηθούν βιολογικά τα μόρια με την χαμηλότερη βαθμονόμηση.Για την σύνθεση των νέων ενώσεων, εφαρμόσθηκαν γνωστές αλλά και τροποποιημένες αντιδράσεις και τεχνικές. Καταβλήθηκε προσπάθεια να βρεθούν μέθοδοι απλές στην εφαρμογή και αποτελεσματικές στην απόδοση. Περιγράφηκαν οι μηχανισμοί των αντιδράσεων. Οι ενώσεις καθαρίστηκαν με διάφορες τεχνικές και ταυτοποιήθηκαν με μεθόδους ενόργανης ανάλυσης. Βρέθηκαν οι φυσικοχημικές ιδιότητες που πρέπει να διαθέτουν τα νέα μόρια(μοριακός όγκος, στερεοχημεία). Οι ενώσεις μελετήθηκαν σε όλους τους πρωτεϊνικούς στόχους που είχαν επιλεχθεί και προσδιορίσθηκε πειραματικά in vitroτο αντιοξειδωτικό τους προφίλ.Τα βιολογικά αποτελέσματά επιβεβαιώνουν ότι οι ενώσεις TH35, TH19,TH31, TH36 και LJ39 αποτελούν πλειοτρόπα υβριδικά παράγωγα. Ειδικότερα, η ένωση TH35 αποτελεί δραστικό αναστολέα των ενζύμων LOX, COX-2 και PDE-2.Οι ενώσεις TH19 και TH31 αποτελούν ισχυρούς αναστολείς της θρυψίνης,της COX-2, της ATX, ενώ η ένωση TH36 είναι δραστικός αναστολέας της COX-2 με ικανοποιητική νευροπροστασία των κυττάρων HT22. Οι αντιοξειδωτικές ιδιότητες δικαιολογούν εν μέρει την ανασταλτική δράση των ενώσεων επί της LOX και COX2.Οι ενώσεις με τον κωδικό LJ μελετήθηκαν για την αναστολή της DNA gyraseτου S. aureus και της τοποϊσομεράσης IV από E. coli και S. aureus. Η ένωση LJ39 παρουσιάζει ιδιαίτερο ενδιαφέρον ως πλειοτρόπο μόριο (ισχυρός αναστολέας COX2),ενώ η LJ24 προκαλεί ισχυρή αναστολή της θρυψίνης.Το υβρίδιο TH18 έδωσε επί 24 ώρες ανοχή στον πόνο που προκαλείται από θερμικό ερέθισμα επηρεάζοντας τον ουδό του πόνου.Οι ενώσεις TH18, TH19 και TH16, παρουσιάζουν τη μεγαλύτερη προσέγγιση"στο ιδανικό φάρμακο"

Boronic Acid Group: A Cumbersome False Negative Case in the Process of Drug Design

Herein we present, an exhaustive docking analysis considering the case of autotaxin (ATX). HA155, a small molecule inhibitor of ATX, is co-crystallized. In order to further extract conclusions on the nature of the bond formed between the ligands and the amino acid residues of the active site, density functional theory (DFT) calculations were undertaken. However, docking does not provide reproducible results when screening boronic acid derivatives and their binding orientations to protein drug targets. Based on natural bond orbital (NBO) calculations, the formed bond between Ser/Thr residues is characterized more accurately as a polar covalent bond instead of a simple nonpolar covalent one. The presented results are acceptable and could be used in screening as an active negative filter for boron compounds. The hydroxyl groups of amino acids are bonded with the inhibitor’s boron atom, converting its hybridization to sp3

Comptes Rendus Chimie 20(4) (2017) 424–434](S1631074816301588)(10.1016/j.crci.2016.05.024)

In this article, the authors wrote wrongfully the cyclization reaction as 5-exo-trig reaction instead of 5-endo-trig cyclization reaction. They apologize to their readers for the inconvenience. © 20172-s2.0-8501987552

alpha-Amination and the 5-exo-trig cyclization reaction of sulfur-containing Schiff bases with N-phenyltriazolinedione and their anti-lipid peroxidation activity

Triazolinedione quenches efficiently the 1,2-dipoles from Schiff bases of glycine esters which are formed via a [1,2-H]-prototropic shift of their alpha-hydrogens, and affords the respective alpha-aminated products in good yields. Competition experiments show a stabilization of the 1,2-dipole from the sulfide substituent. 5-exo-trig cyclization of N-PhTAD with Schiff bases of other amino acids gave triazolines. The antioxidative and lipoxygenase inhibitory activities of the novel synthesized compounds were studied. (C) 2016 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.WOS:0004006562000122-s2.0-8500368090

Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors

In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common component of these regimens. Food and Drug Administration (FDA)-approved NS5A inhibitors, although very potent, do not have the same potency against all eight genotypes of HCV. Therefore, this study aims to synthesize NS5A inhibitor analogues with high potency pan-genotypic activity and high metabolic stability. Starting from an NS5A inhibitor scaffold previously identified by our research group, we made several modifications. Two series of compounds were created to test the effect of changing the length and spatial conformation (para-para vs. meta-meta-positioned bis-imidazole-proline-carbamate), replacing amide groups in the linker with imidazole groups, as well as different end-cap compositions and sizes. The frontrunner inhibits genotype 1b (Con1) replicon, with an EC50 value in the picomolar range, and showed high genotypic coverage with nanomolar range EC50 values against four more genotypes. This together with its high metabolic stability (t½ > 120 min) makes it a potential preclinical candidate