Computer assisted design of potentially active anti-trypanosomal compounds (original) (raw)
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Journal of Molecular Graphics and Modelling, 2006
To explore three possible binding sites of trypanothione and glutathione reductase, namely, the active, the dimer interface and the coenzyme NADPH binding site, a series of eight compounds, nitrofurans and nitrothiophenes derivatives, were docked, using their crystallographic and modeled conformations. Docking results showed that, for both families and both enzymes, compounds are more likely to bind in the interface site, even though there is some probability of binding in the active site. These studies are in agreement with experimental data, which suggest that these class of compounds can act either as uncompetitive or mixed type inhibitors, and also with the finding that there is an a-helix which connects the active with the interface site, thus allowing charge transference between them.
Journal of the Brazilian Chemical Society, 2010
Neste trabalho, uma série de compostos nitro-heterocíclicos foi submetida a estudos químicoquânticos e de voltametria cíclica com a finalidade de determinar as propriedades físico-químicas que exercem influência sobre o potencial redox do grupo nitro. A otimização de estrutura, as propriedades e os mapas de superfícies estereoeletrônicas foram calculadas utilizando o método semi-empírico AM1. O potencial redox dos compostos, Ar-NO 2 /Ar-NO 2 •-, foi determinado em meio aprótico (DMSO e eletrólito de suporte Bu 4 NH 4 BF 4 0,1 mol L -1 ), com o uso de eletrodos de trabalho de carbono vítreo, eletrodo auxiliar de fio de platina e eletrodo de referência de Ag/AgCl. A investigação dos confôrmeros de menor energia mínima demonstrou a ocorrência de quebra de planaridade estrutural entre o nitrogênio hidrazínico e o resíduo benzamídico. Não foi observada a ocorrência de correlação, avaliada através da análise de regressão de PLS, entre as propriedades estereoeletrônicas e o potencial redox, resultado, provavelmente, de quebra da estrutura co-planar no grupo de moléculas estudadas.
… J Research in …, 2011
Tuberculosis is an infection caused by Mycobacterium tuberculosis, which commonly affects the respiratory tract, i.e. lungs. 1) It is termed as "a global health emergency" by World Health Organization (WHO) in 1993 as it affects 1.7 billion people per year that is equal to one-third of the entire world population. The first line of drugs used in the treatment of tuberculosis (TB) is a combination of isoniazid, rifamycin, pyrazinamide and ethambutal. The high concentration of lipids in the cell wall of M. tuberculosis has been attributed to its resistant to antibiotics. Thus the increasing clinical importance of tuberculosis has lent additional urgency to researchers to identify new effective antimycobacterial compounds. 2) Heterocycles bearing nitrogen, sulphur and oxygen atoms in their structure constitute the core structure of a number of biologically interesting compounds. Many indole derivatives reported in the literature are known to possess varied biological activities viz., antimalarial activity, 3) antituberculosis activity 4) and COX-2 inhibitors. 5) Quinolines derivatives have attracted the attention of the chemists because of their presence in many natural products possessing significant biological activities. 6-10) Many indolo[2,3-c]isoquinolines reported from our laboratory have been found to possess bactericidal and fungicidal 11-13) activities. Earlier we have reported the synthesis of 3,5-disubstituted-N b-(2-oxobenzopyran-3-carbonyl)-1H-indole-2-carbohydrazide 14) by making use of ethyl 3-oxo-3-{2-[(5-substituted-3-phenyl-1H-indol-2-yl)carbonyl]hydrazinyl}propanoates 5a, b, which in turn were prepared by the reaction of 5-substituted-3-phenyl-1H-indole-2carbohydrazides 4a, b and diethylmalonate. In view of these findings and in continuation of our research work on indoles, 15-18) we hereby report the synthesis and antimicrobial activity of some 5-substituted-N b-(2-oxo-2H-pyrano[2,3b]quinoline-3-carbonyl)-3-phenyl-1H-indole-2-carbohydrazides 6a-j having indole and pyranoquinoline moieties in their structure with the hope getting compound with more potent antimicrobial and antituberculosis activity by making use of ethyl 3-oxo-3-{2-[(5-substituted-3-phenyl-1H-indol-2-yl)carbonyl]hydrazinyl}propanoates 5a, b and substituted-2-hydroxy-3-formylquinolines 3a-e as starting materials wherein substituted-2H-pyrano[2,3-b]quinoline moiety attached to b-nitrogen of 5-substituted-3-phenyl-1H-indole-2carbohydrazide at its 3-positon via carbonyl group (Chart 1). These compounds are novel and hitherto unknown. Results and Discussion Compounds 5a, b were prepared according to the reported method. 15) These compounds 5a, b when reacted with substituted-2-hydroxy-3-formyl-quinolines 3a-e in the presence of catalytic amount of piperdine in ethanol under refluxed conditions for 5 h afforded 5-substituted-N b-(2-oxo-2Hpyrano[2,3-b]quinoline-3-carbonyl)-3-phenyl-1H-indole-2carbohydrazides 6a-j in a good yield. Compound 6a in its IR spectrum showed absorption bands at 1149, 1597, 1668, 1695, 1733, 3065, 3201 and 3386 cm Ϫ1 due to CO -C, CϭN, CϭO/CϭO/CϭO and NH/NH/NH functions respectively. Three singlets and a multiplet, observed at 9.42, 9.71, 10.20 and 7.14-7.92 d in the 1 H-NMR spectrum of compound 6a were due to one proton of indole NH and two pro
Bioorganic & Medicinal Chemistry Letters, 2009
Novel quinazoline-type compounds were designed as inhibitors of the parasite specific enzyme trypanothione reductase (TR), and their biological activities were evaluated. Some of our compounds inhibited TR, showed selectivity for TR over human glutathione reductase, and inhibited parasite growth in vitro. We propose that the quinazoline framework is a privileged structure that can be purposely modified to design novel TR inhibitors. Furthermore, the use of privileged motifs might emerge as an innovative approach to antiparasitic lead candidates.
European Journal of Medicinal Chemistry, 2017
The rational design and synthesis of a series of 5-nitro-2-furoic acid analogues are presented. The trypanocidal activity against epimastigote forms of Trypanosoma cruzi and the toxic effects on human HeLa cells were tested. Between all synthetic compounds, three of thirteen had an IC 50 value in the range of Nfx, but compound 13 exhibited an improved effect with an IC 50 of 1.0 ± 0.1 µM and a selective index of 70 in its toxicity against HeLa cells. We analyzed the activity of compounds 8, 12 and 13 to interfere in the central redox metabolic pathway in trypanosomatids, which is dependent of reduced trypanothione as the major pivotal thiol. The three compounds behaved as better inhibitors of trypanothione reductase than Nfx (Ki values of 118 µM, 61 µM and 68 µM for 8, 12 and 13, respectively, compared with 245 µM for Nfx), all following an uncompetitive enzyme inhibition pattern. Docking analysis predicted a binding of inhibitors to the enzyme-substrate complex with binding energy calculated in-silico that supports such molecular interaction.