Synthesis of fused heterocyclic aromatic compounds as potential antiplasmodial agents

Jacobs, Leon (2017-12)

Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.

Thesis (PhD)--Stellenbosch University, 2018.

Thesis

ENGLISH ABSTRACT: 3-Methyl benzofuran antiplasmodial compounds have been described in literature and and synthesis of heterocyclic derivatives forms the basis of this project. These benzofuran compounds were synthesized with the primary role as effective inhibitors of the enzyme Plasmodium falciparum N-Myristoyl transferase (PfNMT). PfNMT plays an important enzymatic function in the majority of all living organisms, facilitating the myristoylation of N-terminal glycine residues of proteins that serve many functions in vivo, and is considered vital to the viability of not only most organisms, but P. falciparum too. The rationale behind the key features of these antiplasmodial compounds include the heterocyclic scaffold that induces π – π stacking with amino acid residues at the active site of PfNMT, aromatic amide and ester groups also necessary for π – π stacking and a piperidinium salt coupled to the heterocycle, providing a salt-bridge interaction with neighboring amino acid residues. Five different heterocycles were synthesized with the primary function of replacing the benzofuran moiety in order to ascertain which heterocyclic system is the most efficacious. We synthesized indole, 3-methyl indole, 1-methyl benzimidazole, benzoxazole and benzothiophene scaffolds, each containing an ester group at the C2-position necessary for transesterification and amidation reactions, as well as a phenolic group at the C4-position (C7-position for the benzimidazole scaffold) required for the introduction of a piperidine group. The Boc-protected piperidine group was introduced first, followed by esterification reactions with 2-phenylethanol, benzyl alcohol and 1-naphthalenemethanol. Amidation reactions were also carried out with 2-phenethylamine, benzylamine, 1-naphthylmethylamine and 4-(aminomethyl)pyridine. The synthesis of each series of heterocyclic antiplasmodials was realized after the final Boc-deprotection step, providing all the compounds in salt form. These compounds were sent for whole-cell testing against a P. falciparum chloroquine sensitive strain (NF54) with the intention to prove which heterocycle and aromatic ester or amide substituent improves the efficacy the most, and validate the importance of a methyl group on the 3-methyl indole and 1-methyl benzimidazole scaffold when comparing the efficacy of analogous esters and amides. The results indicated that the benzoxazole series of compounds were inactive and the 3-methyl indole series are the most active which returned IC50 values of 0.56 – 6.1 μM respectively, but is trailed closely in efficacy by the indole (IC50 values of 0.83 – 6.5 μM) and benzothiophene (IC50 values of 0.71 – 5.9 μM) series of compounds. The 1-methyl benzimidazole series of compounds were the least active with IC50 values between 7.4 – 13.3 μM apart from one compound indicating an IC50 value of 1.1 μM.

AFRIKAANSE OPSOMMING: ‘n Versameling van 3-metiel bensofuraan verbindings was ontdek na ‘n literatuur studie uitegrig is, en vorm deel van die doel van die projek wat insluit die sintese van alternatiewe analogiese heterosiekliese verbindinge wat struktureel eenders as die bensofuraan kern molekuul. Die oorpronklike bensofuraan verbindings was gesintetiseer met die doel om ‘n ensiem, Plasmodium falciparum N-myristoïel transferase (PfNMT) te inhibeer. Die funksie van PfNMT is beskou as belangrik en noodsaaklik vir die lewensvatbaarheid van die meerderheid van lewendige organismes, asook vir die parasiet Plasmodium. Die rol van PfNMT sluit in die miristoïelasie van N-terminale glisien aminosuur residue en is beskoou as ‘n goeie teiken vir ensiem inhibisie. Die chemiese redes agter die ontwerp van die vebindings wat gebaseer is op die bensofuraan reeks sluit in die aanwesigheid van die heterosiekliese kern molekuul wat π – π interaksies het met die naasliggende aminosuur residue in die aktiewe setel, die armoatiese ester en amied in C2-posisie wat ook π – π interaksies toon met naasliggende aminosuur residue, en laastens ‘n piperidinium groep wat ‘n sout-brig interaksie vorm met aminosuur residue in die aktiewe setel. Vyf verskillende heteroskikliese verbindings was gesintetiseer wat isostrutureel is met die oorspronklike bensofuraan kern, indool, 3-metiel indool, 1-metiel bensimidasool, bensoksasool asook bensotiofaan. Elke heterosikliese verbinding het n ester groep op die C2-posisie, met die doel om transesterifikasie en amidasie reaksies uit te rig, asook ‘n suurstof atoom by die C4- posisie (C7-posisie op die bensimidasool) wat onderandere gebruik was vir die koppeling met die verkose piperidien groep. Die verbinding van die piperidien groep aan die vyf heterosikliese verbindings was eerste uit gevoer, en gevolg deur die transesterifikasie reaksies met 2-fenieletanol, bensiel alkohol and 1- naftaleenmetanol. Amidasie reaksies was uitevoer met 2-fenieletielamien, bensielamien, 1- naftaleenmetielamien and 4-(aminometiel)piridien. Die finale verbindings van elke heterosikliese reeks was bereik deur middel van ‘n Boc-verwydering op die piperidien groep, wat elke molekuul in soutform los. Die vyf reekse molekules was ingestuur om getoets te word vir aktiwiteit teenoor n chloroquine sensitiewe stam van Plasmodium falciparum (NF54) om te kan onderskei wat se reeks is die mees aktiefste, asook om te onderskei waste aromatiese ester of amied lei na beter aktiwiteit, en laaste, om potensieel te kan bewys dat die metiel groepe aanwesig in die 3-metiel indool en 1- metiel bensimidasool is inderdaad nodig om a verskil in aktiwiteit te toon as analogiese esters en amiede met mekaar vergekyk word. Die resulate het aangetoon dat die bensoksasool reeks van verbindings was onaktief gewees, waarby die 3-metiel indool reeks die mees aktiefste was deur dat dit aktiwiteite tussen 0.56 – 6.1 μM vertoon het. Naaste aan die aktiwiteit van die 3-metiel indool reeks was die indool reeks (IC50 waardes tussen 0.83 – 6.5 μM) en die bensotiofaan (IC50 waardes tussen 0.71 – 5.9 μM). Die 1- metiel bensimidasool reeks het die laagste aktiwitiet betoon met IC50 waardes tussen 0.71 – 5.9 μM behlawe vir een verbinding wat wel n hoe aktiwiteit betoon het van 1.1 μM.

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