Synthesis and structure-antituberculosis activity relationship of 1H-indole-2,3-dione derivatives

• Published in: Bioorganic & medicinal chemistry Vol. 15; no. 17; pp. 5888 - 5904
• Main Authors: KARALI, Nilgün, GÜRSOY, Aysel, KANDEMIRLI, Fatma, SHVETS, Nathaly, BETÜL KAYNAK, F, OZBEY, Süheyla, KOVALISHYN, Vasyl, DIMOGLO, Anatholy
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 01-09-2007
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - toxicity; Biological and medical sciences; Crystallography, X-Ray; Electrons; Hydrogen Bonding; Indoles - chemical synthesis; Indoles - chemistry; Indoles - toxicity; Inhibitory Concentration 50; Medical sciences; Microbial Viability - drug effects; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Structure-Activity Relationship; Nitro compound; Lactam; Morpholine derivatives; Modeling; Structure activity relation; Molecular model; Bacteria; Antituberculous agent; Hydrazone; Chemical synthesis; Electronic-topological method (ETM); Thiosemicarbazone; Prediction; Neural network; Topology; Antituberculosis activity; X ray diffraction; In vitro; Structure- activity relationships; Mycobacterium tuberculosis; Mycobacteriales; Mycobacteriaceae; Actinomycetes; Fluorine Organic compounds; Antibacterial agent; Indole derivatives; 1H-Indole-2,3-diones; Thiazolidine derivatives
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.05.063

New series of 5-fluoro-1H-indole-2,3-dione-3-thiosemicarbazones 2a-k and 5-fluoro-1-morpholino/piperidinomethyl-1H-indole-2,3-dione-3-thiosemicarbazones 3a-r were synthesized. The structures of the synthesized compounds were confirmed by spectral data, elemental and single crystal X-ray diffraction analysis. The new 5-fluoro-1H-indole-2,3-dione derivatives, along with previously reported 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones 2l-v, 1-morpholino/piperidinomethyl-5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones 4a-l, and 5-nitro-1H-indole-2,3-dione-3-[(4-oxo-1,3-thiazolidin-2-ylidene)hydrazones] 5a-s, were evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv. Among the tested compounds, 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones (2p, 2r, and 2s) and its 1-morpholinomethyl derivatives (4a, 4e, 4g, and 4i) exhibited significant inhibitory activity in the primary screen. The antituberculosis activity of molecules with diverse skeletons was investigated by means of the Electronic-Topological Method (ETM). Ten pharmacophores and ten anti-pharmacophores that have been found by this form the basis of the system capable of predicting the structures of potentially active compounds. The forecasting ability of the system has been tested on structures that differ from those synthesized. The probability of correct identification for active compounds was found as equal to 93% in average. To obtain the algorithmic base for the activity prediction, Artificial Neural Networks were used after the ETM (the so-called combined ETM-ANN method). As the result, only 9 pharmacophores and anti-pharmacophores were chosen as the most important ones for the activity. By this, ANNs classified correctly 94.4%, or 67 compounds from 71.