Academic literature on the topic 'Triazole isosters'

Triazoles are five-membered aromatic heterocyclics, which exhibit two isosteric forms (1,2,3-triazoles and 1,2,4-triazoles), as well as multiple applications in medicinal, agricultural, supramolecular, and materials sciences. Famous examples of triazoles include drugs, such as fluconazole, ribavirin, cefatrizine, and tazobactam, as well as herbicides, such as cafenstrole and metosulam. This review aims to present the recent major examples of the application of microwave-assisted organic synthesis (MAOS) to the syntheses and endfunctionalizations of 1,4- and 1,5-disubstituted 1,2,3-triazoles, 1,2,4-triazoles, 3-amino-1,2,4- triazoles, 1,2,4-triazol-3-one, and 1,2,4-triazol-3-thiol derivatives. Notably, the previous reviews on triazole syntheses have not exclusively elucidated the relevance of MAOS techniques in the obtention and derivatization of these compounds.

Motivated by evidence garnered from literature probing the use of triazoles in drug discovery and development, we reported the utilization of bioisosteric replacement and molecular hybridization in this review. Bio-isosteric replacement has played a significant role in modulating rapid and versatile strategy in synthesizing molecules with multifaceted medicinal properties. Molecular hybridization seeks to conjugate two molecular fragments with diverse applications under very mild reaction conditions. In this regard, 1,2,3-triazole is a well-known scaffold with widespread occurrence in medicinal compounds. It is characterized to have several bioactivities such as anti-microbial, anti-cancer, anti-viral, analgesic, anti- inflammatory effects. Furthermore, the structural features of 1,2,3-triazoles enable it to mimic different functional groups justifying its use as bio-isostere for the synthesis of new molecules of medicinal interest, which we have reported briefly.

Pyridine-based gelators 1–4 of triazole-amide isosteric relationship have been considered in metal ion sensing, heavy metal and picric acid adsorption from water. The change from triazole to isosteric amide has marked effect on gelling properties of the gelators.

In this research, a structural variant of muramyl dipeptide (MDP) is designed wherein, the entire N-acetyl group was replaced by a bio-isosteric 1,2,3-triazole moiety with serinol lipid substitution at 4th position. The protecting groups such as benzyl and benzylidine were removed sequentially to evolve three novel derivatives with increasing polarity as seen in the MDP-lipid 21-23 derivatives. A synthesis strategy involving triazolyl click chemistry to combine MDP scaffold to the serinol lipid head group is developed. The new derivatives were characterized using NMR, ESI-MS and MALDI. Preliminary data from in vitro screening of the compounds inferred the immuno-potentiating properties.

C–H glycosylations of complex amino acids and peptides were accomplished through the assistance of triazole peptide-isosteres. The palladium-catalyzed glycosylation provided access to complex C-glycosides and fluorescent-labeled glycoamino acids.

Peptides represent an important class of biologically active molecules with high potential for the development of diagnostic and therapeutic agents due to their structural diversity, favourable pharmacokinetic properties, and synthetic availability. However, the widespread use of peptides and conjugates thereof in clinical applications can be hampered by their low stability in vivo due to rapid degradation by endogenous proteases. A promising approach to circumvent this potential limitation includes the substitution of metabolically labile amide bonds in the peptide backbone by stable isosteric amide bond mimetics. In this review, we focus on the incorporation of 1,4-disubstituted 1,2,3-triazoles as amide bond surrogates in linear peptides with the aim to increase their stability without impacting their biological function(s). We highlight the properties of this heterocycle as a trans-amide bond surrogate and summarise approaches for the synthesis of triazole-containing peptidomimetics via the Cu(I)-catalysed azide-alkyne cycloaddition (CuAAC). The impacts of the incorporation of triazoles in the backbone of diverse peptides on their biological properties such as, e.g., blood serum stability and affinity as well as selectivity towards their respective molecular target(s) are discussed.

Designed binaphthyl-based, cationic peptidomimetic antimicrobials targeting C. difficile, incorporating a click-derived 1,2,3-triazole ester isostere at the C-terminus MICs of 4 μg mL⁻¹ against three human isolates of C. difficile.

Purine isosteres present excellent opportunities in drug design and development. Using isosteres of natural purines as scaffolds for the construction of new therapeutic agents has been a valid strategy of medicinal chemistry. Inspired by the similarity to isoguanine, we attempted to develop a practical method for the preparation of 5-aza-isoguanines. Several synthetic approaches were explored to establish a robust general protocol for the preparation of these compounds. The significant difference in the reactivity of the C-5 and C-7 electrophilic centers of 1,2,4-triazolo[1,5-a][1,3,5]triazines (5-azapurines) towards nucleophiles was demonstrated. The most practical and general method for the preparation of 5-aza-isoguanines involved a regioselective reaction of ethoxycarbonyl isothiocyanate with a 5-aminotriazole. The intramolecular ring closure of the resulted product followed by the S-methylation afforded 7-methylthio-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-one, which could be effectively aminated with various amines. The resulted 5-aza-isoguanines resemble a known purine nucleoside phosphorylase inhibitor and could be interesting for further investigations as potential anticancer agents.

2009/2010
The aspartic protease (HIV-Pr) of the human immunodeficiency virus, responsible agent for AIDS, is surely one of the most studied enzymes in terms of structure and activity. HIV-Pr is responsible for cleaving the viral polyprotein precursor into structural proteins and enzymes and plays an essential role in the viral replication and maturation. HIV-Pr has thus become the target of numerous efforts to design antiviral therapeutic agents suitable for the treatment of AIDS. In the field of organic chemistry, the search for effective HIV-Pr inhibitors has boosted the development of new methodologies for the stereoselective synthesis of compounds containing multiple chiral centers, on which reversible inhibitors are generally based. HIV-Pr shows peculiar characteristics as it is able, unlike any other eukaryotic aspartic protease, to hydrolyze amide bonds with proline as the N-terminal residue. Moreover, it is active in a dimeric form, possessing C2 symmetry, in which each monomer contributes a catalytic aspartate. The first part of the present doctoral work described in Chapter 2, has been dedicated to the synthesis of hydroxyethylene Phe-Pro isosters in which the pyrrolidine ring is expanded by a condensed aromatic ring in order to provide a better fit to the enzyme’s catalytic site. During the synthesis of the isoster a novel reaction was discovered in which enaminones are directly formed by treatment of α,β-unsaturated ketones with trimethylsilylazide and fluoride. Phe-Pro isosters based on the enaminone structure showed moderate activity as HIV-Pr inhibitors. The direct amination of α,β-unsaturated ketones is the subject of Chapter 3. This reaction is demonstrated to be general for enones containing a β-hydrogen. A mechanism based on azide activation via formation of a pentacoordinated silicon species followed by a 1,3-dipolar cycloaddition is proposed and supported by experimental results and calculations. In Chapter 4 is reported the synthesis of a library of triazole inhibitors by a combinatorial approach based on click chemistry. The library was screened for HIV-Pr inhibition and deconvoluted. A set of promising members from the library was synthesized as single, enantiomerically pure compounds that confirmed to be active HIV-Pr inhibitors. Finally, in Chapter 5 the development of an alternative approach to dipeptide isosters, based on the ring closing metathesis of aminoacid-derived allylamines, is described. Building of the four carbon atom backbone of the isosteres is obtained after mounting the olefins on designed linkers that allow selectivity in the cross metathesis, and easy final cleavage. Carbamate linkers will also allow also protection of the amino groups during the next steps of the synthesis leading to the desired di- and monohydroxyethylene isosters.
La proteasi aspartica (HIV-PR) del virus della immunodeficienza umana, l'agente responsabile dell'AIDS, è sicuramente uno degli enzimi più studiati in termini di struttura e di attività. HIV-Pr è responsabile della scissione della poliproteina virale in proteine strutturali ed enzimi e svolge un ruolo essenziale nella replicazione e maturazione del virus. HIV-Pr è così diventato il bersaglio di numerosi studi mirati alla progettazione di agenti terapeutici antivirali adatti per il trattamento dell'AIDS. 
Nel campo della chimica organica, la ricerca di efficaci inibitori dell'HIV-Pr ha stimolato lo sviluppo di nuove metodologie per la sintesi stereoselettiva di composti contenenti più centri chirali, che costituiscono la base strutturale della maggior parte degli inibitori reversibili. 
HIV-Pr presenta caratteristiche peculiari in quanto è in grado, unica tra le proteasi aspartiche da eucarioti, di idrolizzare legami ammidici con la prolina come residuo N-terminale. Inoltre, l’enzima è attivo in una forma dimerica, con simmetria C2, in cui ogni monomero contribuisce con un residuo catalitico di acido aspartico. 
La prima parte del presente lavoro di dottorato, descritta nel capitolo 2, è stata dedicata alla sintesi di isosteri idrossietilenici del dipeptide Phe-Pro, contenenti un anello pirrolidinico espanso al fine di migliorare le interazioni con il sito catalitico dell'enzima. Durante la sintesi dell’ isostere è stata scoperta una nuova reazione di formazione di enaminoni per trattamento di chetoni α,β-insaturi con trimethylsilylazide e fluoruro. Alcuni isosteri Phe-Pro basati sulla struttura enaminonica hanno mostrato una moderata attività come inibitori della HIV-PR. 
L'amminazione diretta di chetoni -insaturi è il soggetto del capitolo 3. Questa reazione si è dimostrata essere generale per enoni contenente un idrogeno in posizione β. Un meccanismo basato sulla attivazione della azide attraverso la formazione di una specie pentacoordinata di silicio seguita da una cicloaddizione 1,3-dipolare viene proposto sulla base dei risultati sperimentali e di calcoli teorici. 
Nel capitolo 4 è riportata la sintesi di una libreria di inibitori triazolici ottenuti con un approccio combinatoriale. La libreria è stato analizzata per l'inibizione di HIV-Pr e deconvoluta. Alcuni membri promettenti della biblioteca sono stati sintetizzati come composti singoli, in forma enantiomericamente pura, confermandosi attivi inibitori della HIV-PR. 
Infine, nel capitolo 5, é descritto lo sviluppo di un approccio alternativo a isosteri di dipeptidi, basato sulla “ring closing methatesis” di allilamine derivate da aminoacidi. La costruzione dello scheletro degli isosteres si ottiene dopo l’assemblaggio delle olefine su un nuovo linker che consente una cross-metatesi selettività nonché un facile distacco del prodotto. Il linker può anche essere utilizzato come gruppo proteggente nella successiva elaborazione sintetica dei prodotti.
XXIII Ciclo
1981

The pawhuskins and schweinfurthins are two classes of stilbene natural product compounds that exhibit interesting biological activity, and because of this they have been studied extensively in our lab through synthetic means. The pawhuskins are a class of small molecule non-nitrogenous opioid receptor modulators that differ significantly in structure from the classical opioid receptor ligands. Some of the natural schweinfurnthins show strong and differential antiproliferative behavior towards a variety of human cancer cell lines. Prior to this research, a significant structure-activity relationship study conducted in our lab has produced a large library of analogues of both classes of compounds. The most potent of theses analogues have served as lead compounds in this study where the stilbene motif present in both classes was substituted with either an amide or triazole linkage. For the new pawhuskin analogues, three of the amide isomers and a triazole isomer synthesized showed antagonist activity for the opioid growth factor (OGF)/opioid growth factor receptor (OGFR) axis which is involved in cellular and organ growth control. This cellular signaling mechanism is targeted by “low-dose” naltrexone therapy which is being tested clinically for multiple sclerosis, Crohn’s disease, cancer, and wound healing disorders. The compounds described here are the first selective small molecule ligands for the OGF/OGFR system and will serve as important leads and probes for further study. For the new schweinfurthins analogues, all compounds synthesized retained antiproliferative activity against similar cancer cell lines to that of the natural compounds. The new amide analogues were produced in pairs only differing in the orientation of the amide linkage replacement for the stilbene motif. Signifigantly greater activity was seen for one orientation of the amide over the other. The synthetic efforts towards all of these analogues will be described herein along with their intriguing biological properties.

L’aminoacyl transférase FemXWv de Weissella viridescens est impliquée dans la biosynthèse du peptidoglycane, composant essentiel de la paroi bactérienne. Cette enzyme est considérée comme une cible attractive pour le développement de nouveaux antibiotiques actifs contre les bactéries multi résistantes. Au cours de ce travail, des analogues du substrat naturel de FemXWv ont été synthétisés permettant d’apporter de nombreuses réponses sur les études mécanistique et structurale de FemXWv. Par la suite, les synthèses des premiers inhibiteurs de transférases Fem ont été réalisées en utilisant une stratégie consistant à remplacer la fonction ester en position 3’ de l’adénosine terminale par des isostères stables de type oxadiazole et triazole. Les analogues stables d’aminoacyl-ARNt se sont révélés être de bons inhibiteurs de FemXWv avec un IC50 compris entre 1 et 4 µM. Enfin, pour étudier le rôle des groupements hydroxyles vicinaux de l’aminoacyl-ARNt, des déoxyanalogues ont été synthétisés. Selon les résultats des tests d’inhibition, nous avons décidé de synthétiser un nouvel inhibiteur contenant le triazole en position 2’ de l’adénosine terminale

In the scope of our BACE1 inhibitor project we used an originally designed microtiter plate-based screening to discover 4 triazole-linked reduced amide isosteres that showed modest (single digit micromolar) BACE1 inhibition. Our ligands were designed based on a very potent (single digit nanomolar) isopththalamide ligand from Merck. We supplanted one of the amide linkages in order to incorporate our triazole and saw a 1000-fold decrease in potency. We then enlisted Molsoft, L.L.C. to compare our ligand to Merck's in silico to account for this discrepancy. They found that the triazole linkage gives rise to a significantly different docking pose in the active site of the BACE1 enzyme, therefore diminishing its potency relative to the Merck ligand. The ability to control the regio- and stereochemical outcome of organic reactions is an ongoing interest and challenge to synthetic chemists. The pre-association of reacting partners through hydrogen bonding (H-bonding) can often to yield products with extremely high stereoselectivity. We were able to show that anilines, due to their enhanced acidity relative to amines, can serve as substrate directing moieties in the opening of cyclohexene oxides. We observed that by judicious choice of conditions we could control the regiochemical outcome of the reaction. These studies demonstrate that an intramolecular anilino-NH hydrogen bond donor can direct Fürst-Plattner epoxide opening. A unified mechanism for this phenomenon has been proposed in this work which consists of a novel mechanistic route we call "NH-directed Fürst-Plattner." We further studied the opening of cyclohexene oxides by incorporating amide and amide derivative substituents in both the allylic and homoallylic position relative to the epoxide moiety. Our attempts to control regioselectivity in the allylic systems were unsuccessful; however when the directing substituent was in the homoallylic position, we could demonstrate some degree of regioselectivity. An additional project that the author worked on for approximately one year during his graduate student tenure is not described within this work. In February of 2009 AstraZeneca, Mayo Clinic, and Virginia Tech Intellectual Properties Inc. concomitantly announced that AstraZeneca licensed a portfolio of preclinical Triple Reuptake Inhibitor (TRI) compounds for depression. The lead compound, PRC200, was discovered by a collaborative effort between the Carlier and Richelson (Mayo Clinic Jacksonville) research groups in 1998. The author was tasked to develop backup candidates of PRC200 in order to improve the pharmacokinetics of the lead compound. Due to confidentiality agreements, this work is not reported herein.
Ph. D.