18F-labelling of new chemotypes for drug discovery

In this thesis, the 18F-labelling of new "chemotypes" will be described with the aim of application in pharmaceutically interesting targets. In Chapter 1, a general introduction to the effect of fluorine substituents on molecular properties and reactivity is provided. This includes the application of organofluorine in both medicinal chemistry and positron emission tomography. Chapter 2 describes a novel silver-mediated 18F-labelling of Ar-SCF3, Ar OCF3 and Ar-OCF2H, including [18F]Riluzole, the 18F labelled version of a drug for treatment of amyotrophic lateral sclerosis (ALS). This work demonstrates that AgOTf can induce halogen exchange nucleophilic 18F-fluorination under mild reaction conditions with a wide range of substrates. In addition, the 18F-labelled Ar-SCF3 substrate is further transformed into the [18F]Umemoto reagent in a single step. The Umemoto reagent has been extensively used for electrophilic trifluoromethylation of various functional groups. Therefore the labelling of this reagent could potentially expand the radiochemical space available for PET applications. To augment the utility of this reagent, we developed a late-stage stereoselective trifluoromethylation-thiocyclisation of alkenes using electrophilic trifluoromethylating reagents such as Umemoto reagent or Togni reagent, which will be discussed in Chapter 3. In this process, thiourea acts as both S-nucleophile and CF3 radical initiator; therefore no metal or photoredox catalyst is required. The reaction affords novel trifluoromethylated 2-amino-thiazolines and 2-amino-thiazines, important scaffolds in the development of aspartate beta-secretase enzyme (BACE–1) inhibitors, a therapeutic target for Alzheimer's disease. Chapter 4 investigates the 18F-labelling of α,α-difluoro-α-aryloxyacetic acid, a class of substrate that can serve as a versatile intermediate which can undergo various decarboxylative functionalisation reactions to afford a wide range of novel 18F labelled α fluorinated aryl ethers. Finally, Chapter 5 gives full experimental procedures and characterisation data for all compounds.</p

18F-labelling of new chemotypes for drug discovery

In this thesis, the 18F-labelling of new "chemotypes" will be described with the aim of application in pharmaceutically interesting targets. In Chapter 1, a general introduction to the effect of fluorine substituents on molecular properties and reactivity is provided. This includes the application of organofluorine in both medicinal chemistry and positron emission tomography. Chapter 2 describes a novel silver-mediated 18F-labelling of Ar-SCF3, Ar OCF3 and Ar-OCF2H, including [18F]Riluzole, the 18F labelled version of a drug for treatment of amyotrophic lateral sclerosis (ALS). This work demonstrates that AgOTf can induce halogen exchange nucleophilic 18F-fluorination under mild reaction conditions with a wide range of substrates. In addition, the 18F-labelled Ar-SCF3 substrate is further transformed into the [18F]Umemoto reagent in a single step. The Umemoto reagent has been extensively used for electrophilic trifluoromethylation of various functional groups. Therefore the labelling of this reagent could potentially expand the radiochemical space available for PET applications. To augment the utility of this reagent, we developed a late-stage stereoselective trifluoromethylation-thiocyclisation of alkenes using electrophilic trifluoromethylating reagents such as Umemoto reagent or Togni reagent, which will be discussed in Chapter 3. In this process, thiourea acts as both S-nucleophile and CF3 radical initiator; therefore no metal or photoredox catalyst is required. The reaction affords novel trifluoromethylated 2-amino-thiazolines and 2-amino-thiazines, important scaffolds in the development of aspartate beta-secretase enzyme (BACEâ1) inhibitors, a therapeutic target for Alzheimer's disease. Chapter 4 investigates the 18F-labelling of &alpha;,&alpha;-difluoro-&alpha;-aryloxyacetic acid, a class of substrate that can serve as a versatile intermediate which can undergo various decarboxylative functionalisation reactions to afford a wide range of novel 18F labelled &alpha; fluorinated aryl ethers. Finally, Chapter 5 gives full experimental procedures and characterisation data for all compounds.</p

Biguanide-Based Synthesis of 1,3,5-Triazine Derivatives with Anticancer Activity and 1,3,5-Triazine Incorporated Calcium Citrate Nanoparticles

Twelve derivatives of biguanide-derived 1,3,5-triazines, a promising class of anticancer agent, were synthesised and evaluated for their anticancer activity against two colorectal cancer cell lines—HCT116 and SW620. 2c and 3c which are the derivatives containing o-hydroxyphenyl substituents exhibited the highest activity with IC50 against both cell lines in the range of 20–27 µM, which is comparable to the IC50 of cisplatin reference. Moreover, the potential use of the calcium citrate nanoparticles (CaCit NPs) as a platform for drug delivery system was studied on a selected 1,3,5-triazine derivative 2a. Condition optimisation revealed that the source of citrate ions and reaction time significantly influence the morphology, size and %drug loading of the particles. With the optimised conditions, “CaCit-2a NPs” were successfully synthesised with the size of 148 ± 23 nm and %drug loading of up to 16.3%. Furthermore, it was found that the release of 2a from the synthesised CaCit-2a NPs is pH-responsive, and 2a could be control released under the acidic cancer environment. The knowledge from this study is perceptive for further development of the 1,3,5-triazine-based anticancer drugs and provide the platform for the incorporation of other drugs in the CaCit NPs in the future

Regio- and stereoretentive synthesis of branched, linear (E)- and (Z)-allyl fluorides from allyl carbonates under Ir-catalysis

This paper describes a new catalytic method for the regio- and stereocontrolled fluorination of allylic carbonates. This transformation uses TBAF·4tBuOH as the fluoride source and [Ir(COD)Cl]2 as the catalyst; the most commonly used [Ir(COD)Cl]2/phosphoramidite system is ineffective. Synthetically, this reaction is characterized by a high degree of structural conservation in going from substrates to the products. The fluorination of (E)-allylic carbonates leading to linear (E)-allylic fluorides (l : b > 20 : 1, E : Z > 20 : 1) is unprecedented and a unique feature of fluoride as the nucleophile. The first examples of transition metal catalyzed fluorination affording (Z)-allyl fluorides (Z : E ratio >20 : 1) are disclosed along with the successful fluorination of branched, linear (E)- and (Z)-allyl carbonates with [18F] fluoride in the presence of [Ir(COD)Cl]2. 18O-Labeling of the reactant reveals internal return during the allylic ionization step, and pathways for effective intra- and intermolecular isotope exchange

FMO-guided design of darunavir analogs as HIV-1 protease inhibitors

Abstract The prevalence of HIV-1 infection continues to pose a significant global public health issue, highlighting the need for antiretroviral drugs that target viral proteins to reduce viral replication. One such target is HIV-1 protease (PR), responsible for cleaving viral polyproteins, leading to the maturation of viral proteins. While darunavir (DRV) is a potent HIV-1 PR inhibitor, drug resistance can arise due to mutations in HIV-1 PR. To address this issue, we developed a novel approach using the fragment molecular orbital (FMO) method and structure-based drug design to create DRV analogs. Using combinatorial programming, we generated novel analogs freely accessible via an on-the-cloud mode implemented in Google Colab, Combined Analog generator Tool (CAT). The designed analogs underwent cascade screening through molecular docking with HIV-1 PR wild-type and major mutations at the active site. Molecular dynamics (MD) simulations confirmed the assess ligand binding and susceptibility of screened designed analogs. Our findings indicate that the three designed analogs guided by FMO, 19–0–14–3, 19–8–10–0, and 19–8–14–3, are superior to DRV and have the potential to serve as efficient PR inhibitors. These findings demonstrate the effectiveness of our approach and its potential to be used in further studies for developing new antiretroviral drugs

Synthesis and Antimicrobial Activity of Novel 4-Hydroxy-2-quinolone Analogs

Alkyl quinolone has been proven to be a privileged scaffold in the antimicrobial drug discovery pipeline. In this study, a series of new 4-hydroxy-2-quinolinone analogs containing a long alkyl side chain at C-3 and a broad range of substituents on the C-6 and C-7 positions were synthesized. The antibacterial and antifungal activities of these analogs against Staphylococcus aureus, Escherichia coli, and Aspergillus flavus were investigated. The structure-activity relationship study revealed that the length of the alkyl chain, as well as the type of substituent, has a dramatic impact on the antimicrobial activities. Particularly, the brominated analogs 3j with a nonyl side chain exhibited exceptional antifungal activities against A. flavus (half maximal inhibitory concentration (IC50) = 1.05 &micro;g/mL), which surpassed that of the amphotericin B used as a positive control. The antibacterial activity against S. aureus, although not as potent, showed a similar trend to the antifungal activity. The data suggest that the 4-hydroxy-2-quinolone is a promising framework for the further development of new antimicrobial agents, especially for antifungal treatment

18F-Labeling of Aryl-SCF3, -OCF3and -OCHF2with [18F]Fluoride

We report that halogenophilic silver(I) triflate permits halogen exchange (halex) nucleophilic 18F‐fluorination of aryl‐OCHFCl, ‐OCF2Br and ‐SCF2Br precursors under mild conditions. This AgI‐mediated process allows for the first time access to a range of 18F‐labeled aryl‐OCHF2, ‐OCF3 and ‐SCF3 derivatives, inclusive of [18F]riluzole. The 18F‐labeling of these medicinally important motifs expands the radiochemical space available for PET applications

Silver-mediated 18F-labeling of aryl-CF3 and aryl-CHF2 with 18F-fluoride

We report the synthesis of [18F]arylCF3 and [18F]arylCHF2 derivatives from arylCF2Br and arylCHFCl precursors applying a silver-mediated halogen exchange with [18F]fluoride. In the absence of Ag(I)OTf, no reaction takes place at room temperature for both classes of substrates; this result demonstrates the beneficial role of silver(I) as a means to induce 18F-incorporation under very mild conditions