Infrared Spectra And Weak Interactions Of Nucleosides And Antibiotics

Antibiotics,as a widely used drug in the clinic,could treat a variety of bacterial and microbial infections which could protect the health of humans and livestock.Nucleoside drugs,known as nucleoside derivatives,also had antibacterial and antiviral effects.Both were often used in combination to treat various viral infections.For example,nucleoside antiviral drugs and antibiotics had been used in combination in the diagnosis and treatment regimen since the outbreak of the new coronary pneumonia（COVID-19）.The position and strength of weak intramolecular and intermolecular interactions,and even the stacking force between unit cells would affect the crystal form of drugs,resulting in differences in drug efficacy and physicochemical properties.How to control weak intramolecular and intermolecular interactions of drug in order to obtain effective crystal forms of drugs had became an important topic.After the drug expires,the structure or crystal form of the drug also would change.Infrared spectrum could reflect the information of functional groups in drug structure,and terahertz spectrum could also reflect the information of crystal form changes caused by weak intramolecular and intermolecular interactions.The combination of the two,as a rapid and nondestructive means,could reflect the changes of drug structure or crystal form to the spectral characteristics at the same time.In this paper,six common antibiotics,four DNA nucleosides and two nucleoside derived drugs were studied by Fourier infrared spectroscopy.Their terahertz（effective frequency range:1-10 THz）and mid infrared spectra(effective frequency range:400-4000 cm^-1)were measured.Based on density functional theory（DFT）,the theoretical calculation of monomer and crystal structure was carried out respectively,and the vibration modes corresponding to all characteristic peaks were obtained.Potential energy distribution（PED）and reduced density gradient（RDG）methods were used to study the changes of weak interaction position and intensity within and between molecules from monomer to polymer,and then to crystal structure.It laid a theoretical foundation for rapid identification of antibiotic drugs,identification of expired antibiotic drugs and control of drug synthesis.The research results were introduced as follows:（1）The terahertz and mid infrared spectra of Ciprofloxacin,Norfloxacin and Ofloxacin were measured and analyzed.Combined with DFT,the theoretical infrared spectra of three antibiotics were calculated with B3LYP/6-311G（d,p）basis set,and the corresponding vibration modes of all characteristic peaks were analyzed.In the terahertz band,it was found that the theoretical calculation was more consistent with the experimental results only when the crystal configuration considering periodic boundary conditions was taken as the configuration.The results showed that the vibration mode in terahertz band came from the collective vibration of molecules,and the hydrogen bond（O-H...:O,N-H...:N）and weak interaction between molecules contributed greatly to vibration modes.In mid-infrared band,the vibration mode at low frequency in the range of 400-800cm^-1still mainly came from the collective vibration of molecules.After 800cm^-1,it mainly showed the vibration and rotation of atoms and groups.（2）Terahertz and mid-infrared spectra were used to study the spectral characteristics of expired and expired Azithromycin,Aevofloxacin Hydrochloride and Ambroxol Hydrochloride drugs.All characteristic peaks of the antibiotics described above were obtained in the infrared spectrum were obtained.Applied density functional theory B3LYP/6-311G++（d,p）basis set to analyze the mid-infrared spectra of these three antibiotics.After theoretical analysis,it was inferred that expired Azithromycin was mainly caused by the changes in theβ-D-hexanopyranosyl and dimethylamino groups.Furthermore,the N-H single bond on the No.7 nitrogen atom in the Ambroxol Hydrochloride structure was broken and expired drugs were oxidized.Combining THz and MIR spectroscopy technology can not only discover whether the molecular structure or crystal form has changed rapidly but also determine what changes have occurred.（3）The terahertz spectra of four DNA nucleosides（guanosine,thymidine,cytidine and adenosine）and two nucleoside derivatives（ribavirin and entecavir）were studied and identified.The terahertz spectra of two nucleoside derivatives were reported for the first time.The vibrational spectra of four kinds of DNA nucleosides and ribavirin crystals were calculated,and all vibrational modes were obtained.And the lattice energy,geometric structure,vibration spectrum of them were analyzed theoretically by the generalized energy-based fragmentation approach under periodic boundary conditions（denoted as PBC-GEBF）and the density functional theory（DFT）.The intra-and intermolecular weak interactions corresponding to the vibrational modes of the crystal,polymer,and monomer were obtained,with the help of the potential energy distribution（PED）and reduced density gradient（RDG）methods.It was found that the sum of electronic and thermal free energies increased from monomer to polymer,and from the polymer to crystal.（4）In order to accurately identify the spectra,we studied the location,type and contribution of all weak interactions,and found that the strong characteristic peaks corresponding to the strong hydrogen bonds came from inter-molecular,while the weak hydrogen bonds mainly originated from within and between molecular,the out-of-plane bending made the largest contribution,accounting for more than 90%.Furthermore,taking guanine,guanosine and two guanosine derivatives（ribavirin and entecavir）as examples,the differences of weak interaction among them caused by different molecular configuration,arrangement and substituent position were studied,and the fundamental reason of THz spectrum change was found.