Electronic structure and physicochemical properties of selected penicillins

Abstract

Traditionally, penicillins have been used as antibacterial agents due to their characteristics and widespread applications with few collateral effects, which have motivated several theoretical and experimental studies. Despite the latter, their mechanism of biological action has not been completely elucidated. We present a theoretical study at the Hartree-Fock and density functional theory (DFT) levels of theory of a selected group of penicillins such as the penicillin-G, amoxicillin, ampicillin, dicloxacillin, and carbenicillin molecules, to systematically determine the electron structure of full ␤-lactam antibiotics. Our results allow us to analyze the electronic properties of the pharmacophore group, the aminoacyl side-chain, and the influence of the substituents (R and X) attached to the aminoacyl side-chain at 6Ј (in contrast with previous studies focused at the 3Ј substituents), and to corroborate the results of previous studies performed at the semiempirical level, solely on the ␤-lactam ring of penicillins. Besides, several density descriptors are determined with the purpose of analyzing their link to the antibacterial activity of these penicillin compounds. Our results for the atomic charges (fitted to the electrostatic potential), the bond orders, and several global reactivity descriptors, such as the dipole moments, ionization potential, hardness, and the electrophilicity index, led us to characterize: the active sites, the effect of the electron-attracting substituent properties and their physicochemical features, which altogether, might be important to understand the biological activity of these type of molecules.

Electrophilicity index within a conceptual DFT framework

“…Philicity also properly accounts for these reactions. 112 Electrophilicity has been connected with several other popular chemical concepts like electronegativity, 113 redox potential, 114 charge transfer descriptor, 65,115 pK a , 116 Hammett s-constant, 117 electron acceptor characteristics, 118 Markovnikov rule, 119 reactivity of paracyclophanes, 120 discolouration reactions, 121 antioxidant properties of phenolic compounds, 122 toxicity of thiadiazoles, 123 organic pesticides, 124 polychlorinated dibenzofurans, 125 phenols (anti-leukemia agents), 126 biochemical activity of 5,6-dihydro-11H-benzo[a]carbazole and its derivatives, 127 structure and properties of penicillins, 128 amino acids 12-26 of TP53, 129 Flavone compounds 130 etc. At a more theoretical level, the electrophilicity has been used to analyze the similarities and differences between the Lewis and Brønsted-Lowry acidity/basicity concepts.…”

“…show reasonable correlation with electrophilicity. Biological activities of sex hormones, 163,173 N-phenyl benzamides 174 (antimicrobial agents), nifurtimox analogues 175 (anti parasitic agents), heme-containing biological systems, 176 phenols (anti-leukeamia agent), 126 5,6-dihydro-11H-benzo[a]carbazole and its derivatives, 127 Penicillins, 128 Flavone compounds, 130 amino acids 12-26 of TP53, 129 polychlorinated dibenzofurans, 125 thiadiazoles, 123 organic pesticides 124 etc. are also correlated with o/o k a .…”

Characterization of electronic structure and physicochemical properties of antiparasitic nifurtimox analogues: A theoretical study

“…It is important to mention that all the studied molecules possess an amide group and hence present acidic properties, except for the NFX molecule which is not acidic and presents trypanocidal activity though [4]. [32]. In group I we may observe that the NFC, NFN, NFI, NBT, NFP, and NFH show a decreasing order of IP.…”

“…Table III collects the values for some calculated global reactivity descriptors such as the ionization potential (IP), hardness (η), the electrophilicity index (ω), and the spatial extent R 2 . The IP may be related with the relative chemical reactivity of the molecules, i.e., larger relative values may indicate lesser oxidative effects 32. In group I we may observe that the NFC, NFN, NFI, NBT, NFP, and NFH show a decreasing order of IP.…”

Electronic Structure and Physicochemical Properties Characterization of the Amino Acids 12−26 of TP53: A Theoretical Study

“…These descriptors have been defined within the density functional theory (DFT) context, and this index has been used to explore variety of application including reactivity, toxicity and drug design. 29,[32][33][34] Thus, we calculated the electrophilicity index (ω) at the same level of theory as the remainder of the previously mentioned global reactivity descriptors, to know the electrophilic nature of the fragments studied here.…”