Design, synthesis, biological and computational studies of flavonoid acetamide derivatives

Author

Daniel Kasungi Isika, New Jersey Institute of TechnologyFollow

Author ORCID Identifier

0000-0003-2874-1903

Document Type

Dissertation

Date of Award

5-31-2023

Degree Name

Doctor of Philosophy in Chemistry - (Ph.D.)

Department

Chemistry and Environmental Science

First Advisor

Omowunmi A. Sadik

Second Advisor

Kevin D. Belfield

Third Advisor

Pier Alexandre Champagne

Fourth Advisor

Yuanwei Zhang

Fifth Advisor

S. Basuray

Abstract

Flavonoid compounds (FC) have extensive biological applications through potent antimicrobial, anti-inflammatory, anticancer, antidiabetic, and antioxidant properties. These applications are nevertheless limited by low bioavailability, poor aqueous solubility, enzymatic degradation, rapid metabolism, and fast body clearance. FC show unique structure-activity relationships (SARs) essential in assessing and mitigating the prevalent challenges impeding their applications. These challenges can be addressed by structural modification of the FC through functionalization of the phenolic rings, modification of the ketone group, and modification of the phenolic hydroxyl groups with bioisosteres.

The objectives of this work are to (i) design and synthesize novel flavonoid acetamide derivatives (FADs) and their analytical characterization using spectroscopic, spectrometric, and chromatographic techniques; (ii) determine the bioavailability and antioxidant capacity of the FADs; (iii) Explore the drug-likeness and the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties using computational tools; and (iv) Determine the SARs on the biological and computational properties of the FC. Novel global and partial FADs of quercetin, apigenin, fisetin, kaempferol, luteolin, and daidzein are synthesized. The global and partial FADs are synthesized with 74.51-81.97% and 49.23-87.23% yields, respectively. The chemical structures are confirmed using ¹H & ¹³C NMR, FT-IR, and UV-Vis characterizations. The molecular weights are determined using ESI-HRMS. The purity of the FADs is 93.40-99.73% as determined using RP-HPLC characterization. The bioavailability of the unmodified flavonoids (UMFs) is 10.78-25.23% while that of the FADs is 15.97-42.59%. The antioxidant capacity, reported as the IC50 values, of the UMFs is 2.19-107.32 μM while that of the FADs is 31.52-217.37μM. The drug-likeness, drug relevance, and ADMET properties are determined computationally. The SARs of the flavonoid compounds are evaluated based on the antioxidant, bioavailability, drug-likeness, and the ADMET properties. The FADs show significantly enhanced bioavailability, but reduced antioxidant capacities, relative to the corresponding UMFs. The FADs have significantly reduced toxicity levels compared to the UMFs. The ADMET properties of the FADs present these compounds as feasible drug candidates. SARs evaluation show that the biological, drug-likeness, and the ADMET properties of FC are a function of the prevalent chemical structures. The applications of FC are inextricably bound to the bioavailability, antioxidant, and toxicity properties analyzed in this study.

Recommended Citation

Isika, Daniel Kasungi, "Design, synthesis, biological and computational studies of flavonoid acetamide derivatives" (2023). Dissertations. 1820.
https://digitalcommons.njit.edu/dissertations/1820