We successfully built structures of metronidazole and ornidazole on Gaussian, both of which we calculated the NMR spectra in chloroform. Additionally, we obtained this data using experimental spectroscopic techniques; this was then compared to the theoretical spectra from Gaussian.
Theoretical proton NMR of metronidazole indicated five different types of hydrogens; Gaussian was unable to differentiate between the hydrogens of the methylene group attached to the imidazole ring, both of which were depicted in two different peaks yet with a degeneracy of one. In comparison, our experimental proton spectra depicted these five peaks more downfield. Gaussian predicted six carbon peaks while experimental NMR resulted in five carbon peaks, three of which were shifted more downfield and two of which were very similar in chemical shifts with Gaussian. The missing peak was the carbon with the nitro group on the imidazole ring.
Gaussian provided a more complex proton NMR for ornidazole, in which the hydrogens on the methyl group and the hydrogen on the hydroxide group were reflected in similar peaks. The hydrogens on the methylene group were also reflected in two peaks. Experimental spectra provided one more hydrogen peak. In contrast to theoretical data, the methyl group was more upfield than the hydroxyl group. Seven different carbons were predicted by Gaussian; experimental spectra indicated some similarities in the chemical shifts of three carbons. The carbon with the nitro attachment on the imidazole ring was reflected in a small peak this time.
With these results we were able to adjust our objectives for the future. Gaussian provided a reasonable theoretical analysis of structural information, and in utilization with experimental spectroscopy, we can determine the reaction mechanism of metronidazole and ornidazole. We want to investigate what the activated complex in the interaction between the drug and the microbe looks like, as well as how it forms. This is particularly an area of interest for ornidazole, which has been verified as more potent than metronidazole because of the smaller amount of drug required to kill a larger number of microbes.
The computational component of this research requires the complex of 2-methyl-5-nitroimidazole ligand and its derivatives, with the salts copper (II) chloride (CuCl2) and nickel chloride (NiCl2). Previously, X-ray diffraction allowed the synthesis of the metronidazole ligand bound to a copper ion. The recently modeled complex of copper-MET is provided below.
Fig. 1. Copper-MET complex
The ligand of the metronidazole drug associates with the transitional metal by its nitrogen atom, containing a lone pair of electrons. The interaction involves the nitrogen acting as a Lewis base to accept electrons from the metal, which acts as a Lewis acid. The nitro group (-NO2) is very reluctant in these interactions. The derivatives of the ligand also behave similarly. The ornidazole ligand is provided below with the pyrole group depicted in planar geometry.
Fig. 2. Ornidazole
This ligand is bound to the nickel chloride.
Fig. 3. Nickel-ORNI complex
The stability of each ligand and its complexed molecule with the transition metals will be tested through Gaussian, specifically the runs including optimization and NMR. The laboratory component involves the synthesis of the complexes by associating metronidazole and ornidazole, as of now, with each metal chloride in methanol, which will then be evaporated. X-ray structures of the crystals will determine relative structures of the interactions.
The objective of this project to investigate donor groups within the anti-microbial drug metronidazole that participate in bonding with metals such as copper, nickel, silver, and zinc. In addition, we would like to identify the mode of action by which enzymes, such as ferredoxins and flavoproteins, might activate the drug in the body. The project will involve a computational and a laboratory component. We will utilize the program Gaussian for the computational part, where we will build the structures of metronidazole and its derivates: dimetridazole, secnidazole, ornidazole, tinidazole, and carnidazole, and then combine them with various metal ions to determine their theoretical activity and stability. The laboratory component will involve the experimental activity of binding the compounds with the metals to form crystal structures of these complexes.
Metronidazole (MET) is an antibacterial and an antiprotozoal drug that is prescribed for trichomoniasis and many other pelvic inflammatory infections. Previous research suggests that metal-complexed MET provides an efficient anti-parasitic effect than MET alone and reports of MET-resistant strains have increased as of 1962, therefore acquiring knowledge of metronidazole activity in the body is vital to improve the composition of the drug in the future and further the treatment of pelvic bacterial infections.
As a sophomore new to research, I hope to build a foundation for chemistry outside of a textbook. The two components of this project are ideal in this endeavor as I will be building structures in a computer and subsequently playing with them in a laboratory. I hope to master Gaussian so I am able to utilize it outside of this project and I hope to increase my knowledge of the interaction between a drug, created by humans, with biological compounds, clearly not created by humans. I also want to learn how scientific projects are devised. For example, what topic does one choose to inform the world? How much research is involved in the process of outlining the methods of the procedure? What are realistic goals for today’s day and age? And ultimately, why is research important?