Browsing by Author "Lovato, Kaitlyn"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Antimicrobial activity of a natural compound and analogs against multi-drug-resistant Gram-positive pathogens
    (American Society for Microbiology, 2024) Shah, Kush N.; Shah, Parth N.; Agobe, Francesca O.; Lovato, Kaitlyn; Gao, Hongyin; Ogun, Oluwadara; Hoffman, Cason; Yabe-Gill, Marium; Chen, Qingquan; Sweatt, Jordan; Chirra, Bhagath; Muñoz-Medina, Ricardo; Farmer, Delaney E.; Kürti, László; Cannon, Carolyn L.
    The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has sparked global concern due to the dwindling availability of effective antibiotics. To increase our treatment options, researchers have investigated naturally occurring antimicrobial compounds and have identified MC21-A (C58), which has potent antimicrobial activity against MRSA. Recently, we have devised total synthesis schemes for C58 and its chloro-analog, C59. Here, we report that both compounds eradicate 90% of the 39 MRSA isolates tested [MIC90 and minimum bactericidal concentration (MBC90)] at lower or comparable concentrations compared to several standard-of-care (SoC) antimicrobials including daptomycin, vancomycin, and linezolid. Furthermore, a stable, water-soluble sodium salt of C59, C59Na, demonstrates antimicrobial activity comparable to C59. C59, unlike vancomycin, kills stationary-phase MRSA in a dose-dependent manner and completely eradicates MRSA biofilms. In contrast to vancomycin, exposing MRSA to sub-MIC concentrations of C59 does not result in the emergence of spontaneous resistance. Similarly, in a multi-step study, C59 demonstrates a low propensity of resistance acquisition when compared to SoC antimicrobials, such as linezolid and clindamycin. Our findings suggest C58, C59, and C59Na are non-toxic to mammalian cells at concentrations that exert antimicrobial activity; the lethal dose at median cell viability (LD50) is at least fivefold higher than the MBC90 in the two mammalian cell lines tested. A morphological examination of the effects of C59 on a MRSA isolate suggests the inhibition of the cell division process as a mechanism of action. Our results demonstrate the potential of this naturally occurring compound and its analogs as non-toxic next-generation antimicrobials to combat MRSA infections
  • Thumbnail Image
    Item
    Developing Greener Methods for the Synthesis of Privileged Structural Motifs and Nitrogen Heterocycles
    (2021-06-07) Lovato, Kaitlyn; Kürti, László
    Efforts towards the development of novel and sustainable methods for the synthesis of privileged scaffolds that are often found in biologically active compounds are described. With the rising interest in green chemistry, the projects highlighted in Part One focused on developing atom economic protocols that minimized the use of transition metal catalysts and eliminated the utilization of harsh/hazardous reaction conditions. In Chapter 1, the investigation of transition metal-free conditions for the α-arylation of activated C(sp3)–H bonds in ester, nitrile, amide, sulfone and diaryl methane substrates is described. The substrate scope of this transformation was thoroughly explored, and a pKa-based reactivity guide was developed. In Chapter 2, the ability for O-cyclopropyl hydroxylamines to function as atom economic, [3,3]-rearrangement precursors for the construction of various classes of heterocycles is presented. An efficient route towards functionalized O-cyclopropyl hydroxylamines and a base-mediated rearrangement protocol for the construction of tetrahydroquinolines are described. Chapter 3 discusses a study conducted in collaboration with Dr. Carolyn Cannon’s group, which reveals naturally occurring biaryl compounds and their structural analogues as potential antimicrobial agents for further investigation. The straightforward synthesis of promising biaryl compounds via an atom economic, organocatalytic and scalable protocol is described. The projects highlighted in Part Two focused on the development of robust methods for the synthesis of nitrogen heterocycles, which are one of the most pervasive structural components in pharmaceutical compounds. Chapter 4 describes a Ti-mediated coupling of oxime ethers and primary alkyl Grignard reagents under Kulinkovich-like conditions to construct previously unreported four-membered nitrogen heterocycles. This work established a one-step protocol for the synthesis of NH-azetidines, which have demonstrated utility in drug discovery and development. In Chapter 5, an investigation into the design and synthesis of a bicyclic scaffold that could function as a next generation para-disubstituted arene molecular mimic is described. A robust protocol for the synthesis of N-substituted bicyclic carbamate scaffolds was developed and these fragments were found to possess comparable substituent geometry to para-disubstituted arenes. This moiety could possess improved aqueous solubility compared to its all-carbon BCP counterpart and has been presented as a promising and novel structural mimic.
  • Thumbnail Image
    Item
    Practical access to axially chiral sulfonamides and biaryl amino phenols via organocatalytic atroposelective N-alkylation
    (Springer Nature, 2019) Lu, Shenci; Ng, Shawn Voon Hwee; Lovato, Kaitlyn; Ong, Jun-Yang; Poh, Si Bei; Ng, Xiao Qian; Kürti, László; Zhao, Yu
    The importance of axial chirality in enantioselective synthesis has been widely recognized for decades. The practical access to certain structures such as biaryl amino phenols known as NOBINs in enantiopure form, however, still remains a challenge. In drug delivery, the incorporation of axially chiral molecules in systematic screening has also received a great deal of interest in recent years, which calls for innovation and practical synthesis of structurally different axially chiral entities. Herein we present an operationally simple catalytic N-alkylation of sulfonamides using commercially available chiral amine catalysts to deliver two important classes of axially chiral compounds: structurally diverse NOBIN analogs as well as axially chiral N-aryl sulfonamides in excellent enantiopurity. Structurally related chiral sulfonamide has shown great potential in drug molecules but enantioselective synthesis of them has never been accomplished before. The practical catalytic procedures of our methods also bode well for their wide application in enantioselective synthesis.
  • Thumbnail Image
    Item
    Transition metal-free direct dehydrogenative arylation of activated C(sp3)–H bonds: synthetic ambit and DFT reactivity predictions
    (Royal Society of Chemistry, 2018) Lovato, Kaitlyn; Guo, Lirong; Xu, Qing-Long; Liu, Fengting; Yousufuddin, Muhammed; Ess, Daniel H.; Kürti, László; Gao, Hongyin
    A transition metal-free dehydrogenative method for the direct mono-arylation of a wide range of activated C(sp3)-H bonds has been developed. This operationally simple and environmentally friendly aerobic arylation uses tert-BuOK as the base and nitroarenes as electrophiles to prepare up to gram quantities of structurally diverse sets (>60 examples) of α-arylated esters, amides, nitriles, sulfones and triaryl methanes. DFT calculations provided a predictive model, which states that substrates containing a C(sp3)-H bond with a sufficiently low pK a value should readily undergo arylation. The DFT prediction was confirmed through experimental testing of nearly a dozen substrates containing activated C(sp3)-H bonds. This arylation method was also used in a one-pot protocol to synthesize over twenty compounds containing all-carbon quaternary centers.