Antifungal effect of 4-arylthiosemicarbazides against Candida species. Search for molecular basis of antifungal activity of thiosemicarbazide derivatives

Abstract

The in vitro antifungal potency of six series of 4-arylthiosemicarbazides was evaluated. Two isoquinoline derivatives with an ortho-methoxy or ortho-methyl group at the phenyl ring were the most potent antifungal agents. Molecular modeling studies and docking of all 4-arylthiosemicarbazides into the active sites of sterol 14α-demethylase (CYP51), topoisomerase II (topo II), l-glutamine: d-fructose-6-phosphate amidotransferase (GlcN-6-P), secreted aspartic proteinase (SAP), N-myristoyltransferase (NMT), and UDP-N-acetylmuramoyl-l-alanine:d-glutamate ligase (MurD) indicated the importance of both structural and electronic factors in ligand recognition and thus for the antifungal effectiveness of 4-arylthiosemicarbazides. A possible antifungal target was identified (NMT) and isoquinoline-thiosemicarbazides showed more favorable affinity than the native ligand.FigureElectrostatic potential surface of isoquiniline derivative compound 6o with antifungal activityElectronic supplementary materialThe online version of this article (doi:10.1007/s00894-012-1420-5) contains supplementary material, which is available to authorized users.

RM1 Semiempirical Model: Chemistry, Pharmaceutical Research, Molecular Biology and Materials Science

“…175 A strategy employed by medicinal chemistry research to obtain energy data of organic compounds that exhibited medicinal activities also included the use of RM1 as the first step of their computational calculations, when, subsequently, DFT and/or ab initio calculations were performed. It is possible to cite the following studies: the conformations of the hypermodified nucleic acid base wybutine, which is predicted to occur at the 37 th position in anticodon loop of tRNA Phe ; 176 the antifungal activities of the derivatives of 4-arylthiosemicarbazides, that can be used against Candida species; 181 conformational analyses of the hypermodified nucleic acid base, mS 2 hn 6 Ade, which is in the 3'-adjacent (37 th ) position in the anticodon loop of the hyperthermophilic tRNAs; 182 conformational studies of the potassium salts of the N-acylhydrazinecarbodithioates, that have antifungal activity; 194 Raman studies to obtain qualitative water content of the skin dermis of healthy young, healthy elderly and diabetic elderly women; 204 and drugs based on complexes of sodium montmorillonite (Na-MMT) and amine-containing drugs (rivastigmine, doxazosin, 5-fluorouracil, chlorhexidine, dapsone, nystatin) that were found to successfully intercalate Na-MMT. 205 In the context of the energetic properties, values of HOMO and LUMO energies were calculated by Tang et al 223 using the RM1 method.…”

Biological evaluation and molecular modelling study of thiosemicarbazide derivatives as bacterial type IIA topoisomerases inhibitors

“…Factors that may limit its antibacterial potency could include lack of penetration of the cell wall or membrane, removal of compound by active efflux mechanisms and alteration of the sensitivity of the target enzyme in its ''biophase'' in the bacterium 25 . In order to determine if any further improvements could be obtained in inhibitory potency and, consequently, in antibacterial activity of the class of thiosemicarbazides, a series of seven 4-benzoyl(aryl)thiosemicarbazides, 3-9, with molecular geometries very similar to that of initial hits 1 and 2 and, for comparison, two 4-aryl(alkyl)-thiosemicarbazides, 10 and 11, of substantially different geometry (Figures 2 and 3) were designed and subsequently prepared using an easy one-step synthesis [26][27][28] (Scheme 1) with commercially available starting materials. Details of experimental procedures and physicochemical characterization of title compounds are given in Supplementary Material.…”

Recent Advances in The Discovery of N‐Myristoyltransferase Inhibitors

“…4-Arylthiosemicarbazide isoquinoline derivatives were acknowledged by Siwek et al [52] as NMT inhibitors with potent antifungal activity. In particular, compound 23, with an ortho-methyl group at the terminal phenyl ring, showed antifungal activity at non-cytotoxic concentrations in mammalian cells with an MIC value of 50 mg mL À1 against C. albicans.…”