A series of novel 5-[1-aryl-1,4-dihydro-6-methylpyridazin-4-one-3-yl] -2-arylamino-1,3,4-oxadiazoles, fungicidally active, were synthesized based on bioisosterism and tested in vivo against wheat leaf rust, Puccinia recondita. These compounds were shown to be fungicidally active, and their activity was influenced by the nature of the substituents. By using the three-dimensional quantitative structure-activity relationships (3D-QSAR) method of comparative molecular field analysis (CoMFA), we have studied the structure and activity relationship of the compounds containing both pyridazinone-substituted 1,3,4-thiadiazoles and pyridazinone-substituted 1,3,4-oxadiazoles. The 3D-QSAR modes gave good correlation between the variations on percent inhibition and the steric-electrostatic properties. The results are consistent with a common mode of action for the pyridazinone-substituted 1,3,4-thiadiazoles and the pyridazinone-substituted 1,3,4-oxadiazoles, which further confirms that the 1,3,4-oxadiazole ring is a bioisosteric analogue of the 1,3,4-thiadiazole ring. These offer important structural insights into designing highly active compounds prior to their synthesis.

Synthesis and Biological Activity of 1,3,4-Oxadiazole-Substituted Pyridazinones.-Two alternative routes for the synthesis of novel oxadiazolyl-substituted pyridazinones [cf. (IV), (VI)] starting from pyridazinylhydrazides (I) are developed. Preliminary tests show that these compounds exhibit high antifungal activity.

Several 1-(1-aryl-1,4-dihydro-3-carboxy-6-methylpyridazin-4-one)-4-aryl thio-semicarbazides and their corresponding oxadiazole, thiadiazole and triazole derivatives were prepared and characterized by their spectral data. The preliminary biological tests showed that some new compounds exhibit good anti-fungal activity.J. Heterocyclic Chem., 38, 993 (2001).Acylthiosemicarbazides and their related heterocyclic derivatives are reported to show a broad spectrum of biological activities. Some of these compounds have been shown to exhibit bactericide, fungicide and plant growtheffecting properties [1,2,3]. These observations, and our interest in 1-aryl-1,4-dihydro-3-carboxy-6-methylpyridazin-4-one chemistry [4], prompted us to undertake the synthesis of an, as yet unreported series of 1-(1-aryl-1,4-dihydro-6-methylpyridazin-3-carboxy-4-one)-4-aryl thiosemicarbazides 2a-c and their corresponding thiadiazole 3a-c, oxadiazole 4a-c and triazole 5a-c, 6a-c derivatives which are novel tri-heterocyclic compounds in order to studying their biological properties.The starting material, hydrazide of 1-aryl-1,4-dihydro-6-methylpyridazin-3-carboxy-4-one 1 obtained according to the literature [5,6,7], which was reacted with various arylisothiocyanates afforded the acylthiosemicarbazides 2a-c [8,9,10]. The treatment of 2a-c with concentrated sulfuric acid yielded the corresponding 1,3,4-thiadiazoles 3a-c, while the treatment of 2a-c with Hg(OAc) 2 resulted in the formation of 1,3,4-oxadiazoles 4a-c. The corresponding substituted 1,2,4-triazoles 5a-c were obtained by reacting 2a-c with sodium carbonate. The thioethers 6a-c were prepared by reaction of thiones 5a-c with iodomethane in sodium hydroxide, preferably with addition some non-homogeneous catalyst, for example tetrabutylammonium ion. (Scheme 1)

Lung cancer is still the predominant cause of cancer-associated mortality worldwide. The bone metastasis of lung cancer brings great suffering to the patient. Previous advances have provided insights into the mechanism of bone metastasis. Previous research has investigated lung cancer stem cells and three steps were determined for the lung cancer cells to metastasize to the bone: i) Escaping from the primary tumor; ii) moving in the circulation; iii) colonizing in the bone. Key molecules are involved in each of these process. Although there is a close association and similarity, dynamic microenvironments affect these processes. The receptor activator of nuclear factor-κB (RANK)/RANKL axis serves a vital role in the regulation of the generation and activation of osteoclasts during the osteolytic lesion. However, the specific molecules for the lung cancer cells to metastasize to the bone require further research and exploration. The present study aimed to investigate the relative molecular mechanisms of bone metastasis in lung cancer in recent years, providing a general understanding about the features of lung cancer preferences to bone, and discussing other things that require investigation.