We report that phthalimides may be cyclized using a Mukaiyama-type aldol coupling to give variously substituted fused lactam (1,2,3,9b-tetrahydro-5
-pyrrolo2,1-
isoindol-5-one) systems. This novel ...process shows a high level of regioselectivity for
-substituted phthalimides, dictated by steric and electronic factors, but not for
-substituted phthalimides. The initial aldol adduct is prone to elimination, giving 2,3-dihydro-5
-pyrrolo2,1-
isoindol-5-ones, and the initial cyclisation can be conducted in such a way that aldol cyclisation-elimination is achievable in a one-pot approach. The 2,3-dihydro-5
-pyrrolo2,1-
isoindol-5-ones possess cross conjugation and steric effects which significantly influence the reactivity of several functional groups, but conditions suitable for epoxidation, ester hydrolysis and amide formation, and reduction, which provide for ring manipulation, were identified. Many of the derived lactam systems, and especially the eliminated systems, show low solubility, which compromises biological activity, although in some cases, antibacterial and cytotoxic activity was found, and this new class of small molecule provides a useful skeleton for further elaboration and study.
Enzyme inhibitors working by
O
-acylation of nucleophilic serine residues are of immense medicinal importance, as exemplified by the β-lactam antibiotics. By contrast, inhibition of nucleophilic ...cysteine enzymes by
S
-acylation has not been widely exploited for medicinal applications. The SARS-CoV-2 main protease (M
pro
) is a nucleophilic cysteine protease and a validated therapeutic target for COVID-19 treatment using small-molecule inhibitors. The clinically used M
pro
inhibitors nirmatrelvir and simnotrelvir work
via
reversible covalent reaction of their electrophilic nitrile with the M
pro
nucleophilic cysteine (Cys145). We report combined structure activity relationship and mass spectrometric studies revealing that appropriately functionalized γ-lactams can potently inhibit M
pro
by reversible covalent reaction with Cys145 of M
pro
. The results suggest that γ-lactams have potential as electrophilic warheads for development of covalently reacting small-molecule inhibitors of M
pro
and, by implication, other nucleophilic cysteine enzymes.
Thiophene-fused γ-lactams are reversible covalent inhibitors of the SARS-CoV-2 main protease, a nucleophilic cysteine enzyme. γ-Lactams can inhibit nucleophilic cysteine enzymes by
S
-acylation as well as nucleophilic serine enzymes by
O
-acylation.
Enzyme inhibitors working by
-acylation of nucleophilic serine residues are of immense medicinal importance, as exemplified by the β-lactam antibiotics. By contrast, inhibition of nucleophilic ...cysteine enzymes by
-acylation has not been widely exploited for medicinal applications. The SARS-CoV-2 main protease (M
) is a nucleophilic cysteine protease and a validated therapeutic target for COVID-19 treatment using small-molecule inhibitors. The clinically used M
inhibitors nirmatrelvir and simnotrelvir work
reversible covalent reaction of their electrophilic nitrile with the M
nucleophilic cysteine (Cys145). We report combined structure activity relationship and mass spectrometric studies revealing that appropriately functionalized γ-lactams can potently inhibit M
by reversible covalent reaction with Cys145 of M
. The results suggest that γ-lactams have potential as electrophilic warheads for development of covalently reacting small-molecule inhibitors of M
and, by implication, other nucleophilic cysteine enzymes.
Chapter I gives brief history of drug discovery and development for anticancer and antibacterial agents with discussion on the reported mode of actions for each class of compounds. In the search for ...novel anticancer and antibacterial agents, UCS1025A is introduced, with a detailed review for all the published total synthesis, biosynthesis and SAR of analogues of UCS1025A. Chapter II focuses on expanding methodology for imide synthesis successfully employing solventless reactions conditions with quantitative conversions. The latter section explores esterification of acid containing imides and problems associated with Michael addition. Chapter III expand on the use of TBDMSiOTf, by subjecting ester containing maleimides and phthalimides to silyl triflate-mediated soft-enol cyclisations to form both bi- and tricyclic systems, while giving comprehensive structural analysis. This chapter also explores the potential stability, solubility and potential for elaboration of these systems. Chapter IV expands the chemistry introduced in chapter III by incorporating substituted maleimides and phthalimides to TBDMSiOTf-mediated cyclisations and starts to explore the possibility of elaboration on the lactam ring. Nitriles are shown to be a worthy replacement for esters in a novel modification to these cyclisations. Part of this chapter focus on the synthesis of a tricyclic system via the elimination of the silyl appendaged group to afford a unique and completely flat pyrrolidone. Chapter V looks at manipulating the alkene previously synthesised by various methods such as epoxidation and hydrogenation to remove the flatness seen in these compounds to aid the lack of solubility. Lastly, this chapter attempts to further diversify these compounds by Suzuki couplings and attempts at CH arylation using bi-dentate directing groups. Chapter VI reports biological activity for the compounds tested, when applicable, for their potential anticancer and antibacterial activity.
