The ergosterol biosynthetic pathway, vital for the membrane structure, serves as a target for azole-class antifungals. The development of azoles, from the rst­generation ketoconazole to the third-generation agents like voriconazole and posaconazole, represents a milestone in combating fungal infections. We also observe the structural and functional relationship between the various side chain modications. We observed the upgradation from a two nitrogen imidazole system to a three nitrogen triazole system, signicantly increased the resistance of the drugs to acid and alkaline hydrolysis, as evidenced in uconazole compared to ketocon­azole. Also, with the introduction of more electronegative halogens like uorine, there is further increase in the binding of the antifungals with the CYP51. By inhib­iting the fungal cytochrome p450 enzyme (CYP51 or Erg11), azoles disrupt ergos­terol biosynthesis, contributing to their efcacy. The CYP51 or Erg11 is the fungal cytochrome p450 and is responsible for xenobiotic degradation. Also, this enzyme is responsible for the ergosterol biosynthesis. Thus, by function, even though the CYP51 tries to clear the xenobiotic azole, in turn it gets inhibited by azole itself. Now, the question arises why it is not able to be metabolized azole by the CYP51 like any other xenobiotic? Well, the answer lies in the mechanism. In the resting state, cytochrome, a water molecule, remains bound to the heme moiety of CYP51. The azole moiety of the drug breaks the hydrogen bonding between water and heme by forming a pentacoordinate bond. This strong binding hampers electron transfer to and oxygen binding further, and thus, the CYP51 could not perform oxidation and thus could not break the cyclic structures (Balding etal. 2008).