Fat-based Dual-branch Triazolo Synthesis And Biological Activity Of Oxadiazole-aryl Derivatives Of Thiophene

The method of cyclization, derivative types and introduction of pharmacophore feature functionalgroup of the1,2,4-triazole were reviewed. Forty two target products bis[3-alkyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole-6-yl]aryls were designed and synthesized, in which thirty four new compounds were firstsynthesized. Corresponding characterization and pharmaceutical activity tests were carried out for all targetaliphatic substitutes. Specific studies as follows:First,3-substituted triazoles have been confirmed as a special function, and efficacy of pharmacophorefragments which have superior performance. But many drugs with this fragment always occupy3-aromaticgroups, which have brought the poor solubility and the lower pharmacodynamics. Therefore, the reactionused six kinds of aliphatic acids as starting materials, including n-octanoic acid, decanoic acid, lauric acid,myristic acid, palmitic acid and stearic acid which have low melting points. Reacted with diaminothioureautilizing fusion method and cyclozation, six3-aliphatic-1,2,4-triazole derivatives2(a-f) were synthesizedin high yields, wherein2e and2f were synthesized for the first time.Second, according to structure-activity relationships (SAR), a novel series of fused heterocyclicderivatives which obtained3-aliphatic substituted-1,2,4-triazoles and aromatic thiadiazoles wereconstructed in order to have high pharmaceutically activity and good solubility. Thirty six targetcompounds were afforded by reacting3-alkyl-4-amino-5-mercapto-1,2,4-triazolo2(a-f) with three kindsof organic acids (isonicotinic acid and2,6-pyridinedi carboxylic acid, isophthalic acid and terephthalic acid,2-aminoterephthalic acid and5-aminoisphthalic acid) respectively, using phosphorus oxychloride ascatalysis. Excepted for the isonicotinic acid derivatives3(a-d), the other32compounds are newcompounds.In order to compare the change of the pharmaceutically activity and solubility of3-aliphatic targetcompounds with3-aromatic compounds in detail, the cyclozation of15with the above-mentioned threekinds of organic acids were performed and afforded6kinds of bis[3-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole-6-yl] aryl derivatives (10-14), wherein compound10and11were first synthesized. These42target compounds were characterized successfully by1H NMR，IR and HRMS techniques. As a result, thepharmaceutically activity and solubility of3-aliphatic target compounds contrasted to3-aromatic typesshowed greatly improved and amino group had obviours inflution on pharmaceutically activity. As aconclution,3-aliphatic target compounds may be the better potential drugs. This enlarged the bolting fieldof this type drugs.Third, the inhibitory properties of CDC25B and PTP1B were choosed to study in the biologicalactivity screening. The results of the inhibition rates test showed that42new nitrogen heterocyclic targetshave different degree inhibition, wherein compounds4(a-f)、5a、5b、5d、7(a-f)、8a、10and11showedpotent CDC25B inhibiting activities, the highest inhibition rate reached100%; compounds4e、4f、7a、7c、7d and7f showed potent PTP1B inhibiting activities, the highest inhibition rate reached99.72%.