TY - JOUR
T1 - Selectivity in the Formation of Straight-Chain Versus Cyclised Products on Knoevenagel Condensation Between Thiobarbituric Acid and Naphthaldehydes
AU - Fraser, William
AU - Haddad, Abdullah
PY - 2021/9/1
Y1 - 2021/9/1
N2 - The prevalence of Clostridium difficile (CD) infection has grown rapidly due to resistance and the emergence of new, highly virulent strains of the organism that have become less sensitive to many antibiotics. Vancomycin and metronidazole are front-line treatments of CD infection that still show good efficacy, but their effectiveness has declined for the treatment of recurrent infection and less sensitive strains of CD. More recently, the macrolide antibiotic fidaxomicin been introduced in the treatment of CD infection. Its high cost and limited usefulness against recurrent infection has prompted the search for new, narrow spectrum agents. We identified the CD dihydroorotate dehydrogenase (DHODase) as a potential enzyme target for the design of Knoevenagel products formed from reaction of 2-thiobarbituric acid and naphthaldehyde substrates. The presence of a hydroxyl substituent at position C2 in the naphthaldehyde ring offers the possibility to form the Knoevenagel product and to cyclize to give the tetracyclic, oxadeazaflavine with benzo-homologation. In this work, the selectivity for straight-chain formation over competing cyclisation on Knoevenagel condensation between thiobarbituric acid and naphthaldehyde substrates was examined. The outcomes of uncatalyzed condensations in refluxing ethanol were investigated by various methods including high field
1H and
13C NMR. Unsubstituted naphthaldehyde and its 2-methoxyl derivative favored straight-chain product formation whereas use of 2-hydroxynaphthaldehyde favored cyclisation and concomitant Michael addition of a second molecule of the corresponding acid to the newly formed exocyclic C=C bond. The pattern of reactivity was mirrored in the benzaldehyde series where the presence of the 2-hydroxyl function led to cyclized products with concomitant formation of the Michael adducts. The Knoevenagel products and the benzo-homologated oxadeazaflavine derivatives are candidates for evaluation as potential growth inhibitors of CD.
AB - The prevalence of Clostridium difficile (CD) infection has grown rapidly due to resistance and the emergence of new, highly virulent strains of the organism that have become less sensitive to many antibiotics. Vancomycin and metronidazole are front-line treatments of CD infection that still show good efficacy, but their effectiveness has declined for the treatment of recurrent infection and less sensitive strains of CD. More recently, the macrolide antibiotic fidaxomicin been introduced in the treatment of CD infection. Its high cost and limited usefulness against recurrent infection has prompted the search for new, narrow spectrum agents. We identified the CD dihydroorotate dehydrogenase (DHODase) as a potential enzyme target for the design of Knoevenagel products formed from reaction of 2-thiobarbituric acid and naphthaldehyde substrates. The presence of a hydroxyl substituent at position C2 in the naphthaldehyde ring offers the possibility to form the Knoevenagel product and to cyclize to give the tetracyclic, oxadeazaflavine with benzo-homologation. In this work, the selectivity for straight-chain formation over competing cyclisation on Knoevenagel condensation between thiobarbituric acid and naphthaldehyde substrates was examined. The outcomes of uncatalyzed condensations in refluxing ethanol were investigated by various methods including high field
1H and
13C NMR. Unsubstituted naphthaldehyde and its 2-methoxyl derivative favored straight-chain product formation whereas use of 2-hydroxynaphthaldehyde favored cyclisation and concomitant Michael addition of a second molecule of the corresponding acid to the newly formed exocyclic C=C bond. The pattern of reactivity was mirrored in the benzaldehyde series where the presence of the 2-hydroxyl function led to cyclized products with concomitant formation of the Michael adducts. The Knoevenagel products and the benzo-homologated oxadeazaflavine derivatives are candidates for evaluation as potential growth inhibitors of CD.
KW - Clostridium difficile
KW - Knoevenagel Condensation
KW - Naphthaldehyde
KW - Thiobarbituric acid
UR - https://rjptonline.org/HTMLPaper.aspx?Journal=Research%20Journal%20of%20Pharmacy%20and%20Technology;PID=2021-14-9-66
UR - http://www.scopus.com/inward/record.url?scp=85116049178&partnerID=8YFLogxK
U2 - 10.52711/0974-360X.2021.00852
DO - 10.52711/0974-360X.2021.00852
M3 - Article
SN - 0974-3618
VL - 14
SP - 4903
EP - 4908
JO - Research Journal of Pharmacy and Technology
JF - Research Journal of Pharmacy and Technology
IS - 9
ER -