Isoniazid Essay

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ISONIAZID Isoniazid was identified by pursuing derivatives of nicotinamide. Optimization of nicotinamide produces two distinct drugs with very different charactetistics, rifampin and pyrazinamide. There are two independent tracks of SARs for this drug series, one governing the activation of the prodrug and another governing the interaction of the active species with InhA. Many groups at the 4-position can be activated inside M.tubeculosis, and are possible prodrug structures. After activation, the structural requirments for InhA binding appear to be very stringent. Only the isonicotinoyl core structure is substantially active among many aryl and heteroaryl groups explored. The isonicotinoyl group could be substituted with lower alkyl groups while…show more content…
[47] Chemical modifications of the natural products have produced several clinically important semisynthetic rifamycins with improved pharmacological profiles. SARs are highlighted in the figure below. Pyrazinamide is one of the analog of nicotinamides and shares the same root with isoniazid. It can be only activated under acidic condition. There are two ways of the SAR tracks, which are the activation of the pyrazinamidase (PZase) and also the target interaction of the resulting acid. [46] In the study of Structure-activity relationship, the R1 groups contribute to two important functions: i. The activated species of pyrazinamide, pyrazinoic acid is usually in its anionic form at physiological pH. Thus, it is not permeable or bioavailable. With R1 group, it can masks the acid group and makes the drug permeable to cell membranes. [46] ii. The killing effect of pyrazinoic acid is unlikely a selective process. The presence of R1 group will cause the selective removal of R1 group by M.tuberculosis and other bacteria. Hence, this will lead to desired selectivity of the drug.
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