1,2,4-oxadiazole bioisostere

Oxadiazoles owe their importance mainly to their biological activities. A basic idea behind many developments is that the 1,2,4-oxadiazole ring is a hydrolysis resisting bioisosteric replacement for an ester functionality <90JMC1128,91JMC140,91QSAR109>. 

The 1,3,4-oxadiazole moiety, in analogy to the 1,2,4-oxadiazole discussed in Section 11.2.5.1, has been used extensively as an ester or amide bioisostere, but also has only recently been applied as an amide replacement in actual peptide segments.1104-1071 The synthesis of the peptide surrogate 1,3,4-oxadiazole derivative 60 is shown in Scheme 18.11021 The N-protected amino acid Boc-Ala-OH (56) was coupled with ethanol to form the ester 57 which was subsequently reacted with hydrazine to form the amino acid hydrazide 58.11(1X1 The hydrazide 58 was reacted with ethyl oxalyl chloride at — 30 °C to room temperature to provide the diacylhydrazide 59. This intermediate was subsequently dehydrated with thionyl chloride in refluxing toluene to form the desired 1,3,4-oxadiazole 60 in >95% ee. Although the overall yields are only moderate, the reported enantioselectivities of the final compounds are very good (Table 4).11021... 

The 1,2,4-triazole moiety, like the 1,2,4-oxadiazole and 1,3,4-oxadiazole discussed in Section 11.2.5, has been used extensively as an ester or amide bioisostere but has rarely been inserted into peptide segments 109-112 1,2,4-Triazoles are complementary to the 1,2,4- and 1,3,4-oxadiazoles due to their ability to donate a hydrogen bond as well as accept a hydrogen bond. 

Glaxo scientists have reported on a new series of H3 antagonists that contain a 1,2,4-oxadiazole ring as a bioisostere equivalent of the isothiourea functionality of... 

For the first time, the 1,2,4-oxadiazole ring has been used as a bioisosteres of the ester group in the field of nucleotide chemistry for the production of inhibitors of the bacterial cell-wall synthesis like compound 171.<07JA12642>. 

On the basis of this equation Zou et al. have concluded that hydrophobic compounds with inductively electron-donating ortho substituents would be favorable for the activity [193]. In continuation of this, Zou and coworkers have carried out CoMFA-based 3D-QSAR analysis of these compounds together with 5-[l-aryl-l,4-dihydro-6-methylpyridazin-4-one-3-ylj-2-arylamino- 1,3,4-oxadiazoles [ 194]. Here also the antifungal activity of these compounds has been found to be well explained by their steric and electrostatic properties. In addition to this, it has confirmed the bioisosterism... 

Replacement of the methyl ester moiety of the muscarinic partial agonist arecoline (16) by the putative nonclassical bioisosteric 1,2,4-oxadiazole ring system (18), where R = un-... 

In an alternate strategy to provide resistance to in vivo ester cleavage of arecoline (187), bioisosteric replacement of the methyl ester groups of arecoline and norarecoline by a 3-alkyl-1,2,4-oxadiazole ring (151)was investigated (188). 

In continuation of efforts to identify Mi-selective muscarinic agonists capable of crossing the blood-brain barrier, the 3-carbo-methoxy group of arecoline was replaced by bioisosteric 1,2,5-oxadiazole (154) or by 1,2,5-thiadiazole rings with oxygen ether substituents at position 3 (155)or with thioether substituents at position 3 (156) (190). 

Later 1,2,4-oxadiazoles have been used mainly as bioisosteric replacements of esters and amides (1994JMC2421, 1999JMC4331), and only recently have they been introduced as an essential part of a pharmacophore. In general, 1,2,4-oxadiazoles are flat, aromatic linkers able to give a bending to a drug s structure, and also exert an electron-withdrawing efiect. 

Andersen K, Lundt B, Joegensen A, Braestrup C (1996) Oxadiazoles as bioisosteric transformations of carboxylic functionalities. II. Eur J Med Chem 31 417-425... 

Oxetane 8-amino acids and their 5-azido ester precursors have been submitted to a number of transformations, showing the synthetic potential of these stmctures. 1,2,4-Oxadiazole, commonly used as bioisosteric replacement for amides, esters, and isothioureas [38] was introduced into stmctures type 103 [39] (Scheme 4.16). 

---