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

Abstract

American trypanosomiasis, also known as Chagas' disease, is caused by Trypanosoma cruzi (T. cruzi). It is well known that trypanosomes, and particularly T. cruzi, are highly sensitive towards oxidative stress, i.e., to compounds than are able to produce free radicals. Generally, nifurtimox (NFX) and benznidazol are most effective in the acute phase of the disease; therefore, nitroheterocycles constitute good models to design other nitrocompounds with specific biological characteristics. Thus, we have performed an ab initio study at the Hartree-Fock and Density Functional Theory levels of theory of several NFX analogues recently synthesized, to characterize them by obtaining their electronic, structural, and physicochemical properties, which might be linked to the observed antichagasic activity. The antitrypanosomal activity scale previously reported for the NFX analogues studied in this work is in good agreement with our theoretical results, from which we can conclude that the activity seems to be related to the reactivity along with the acidity observed for the most active molecules.

Electrophilicity index revisited

“…Toxicity of various aliphatic and aromatic compounds 301 against a protozoa, Tetrahymena pyriformis , 302 and ecotoxicity towards a fish species, Pimephales promelas , 303 are also studied. Toxic behavior of cis‐platinum(II) complexes, 304 alkenes, 305,306 pyrido‐di‐indoles, 307 electrophilic sugars, 308 and so forth, and biological activities of sex hormones, 297,309 heme‐systems, 310 antimicrobial, 311 anti‐leukeamia, 171 and anti‐parasitic agents, 312 organic pesticides, 174 Penicillins, 180 thiadiazoles, 177 and so forth. are also correlated with ω and its local counterparts.…”

Update 2 of: Electrophilicity Index

“…Electrophilicity index has also been made use of in analyzing antitumoral activity of synthetic chalcones, cis -platinum complexes, , testosterone derivatives, synaptosomal toxicity of 4-hydroxyl-2-nonenal, toxicity of PCDDs, hemolytic activity of methacrylates, activation of AhR by some biphenyls, metal-binding specificity of porphyrins, effect of plant growth regulators on chloroacetanilide herbicides, reactivity of porphyrin pincers, mutagenic activity of dinitrobenzo[a]pyrene isomers, activities of nonbenzodiazepine compounds, radical-scavenging activity of flavones, cancer-cell membrane lysis properties of peptides like PNC- 27, different sulfonamides as carbonic anhydrase inhibitors against isozyme, CA-II, skin sensitization potential of alkenes, , arsenic toxicity, toxicity of electrophilic sugars, pyridodiindoles, etc. Biological activities of N -phenyl benzamides (antimicrobial agents) and nifurtimox analogues (antiparasitic agents) are also correlated with electrophilicity and its local variants.…”

Electrophilicity index within a conceptual DFT framework

“…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 .…”