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Methods and Principles in Medicinal Chemistry - Mannhold R.

Mannhold R., Kubinyi H., Timmerman H. Methods and Principles in Medicinal Chemistry - Wiley-VCH, 2001. - 155 p.
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Fig. 8.21 Structures of vesnarinone, and its major metabolite veratrylpiperazinamide. The pathway metabolized by activated neutrophils gives rise to two highly reactive species, an iminium ion and a quinone imine.
Sulphonamide antimicrobial agents (Figure 8.22) such as sulphamethoxazole [21] are oxidized to protein-reactive cytotoxic metabolites in the liver and also other tissues. These include hydroxylamines and further products such as nitroso-deriva-tives. Sulphonamide drugs are linked with agranulocytosis, aplastic anaemia and
Fig. 8.22 Structures of sulfamethoxazole and dapsone, drugs which form toxic hydroxylamine metabolites.
112 8 Toxicity
skin and mucous membrane hypersensitivity reactions including Stevens-Johnson syndrome, and others. Dapsone [22] is a potent anti-inflammatory and anti-parasitic compound, which is metabolized by cytochrome P450 to hydroxylamines, which in turn cause methaemoglobinemia and haemolysis.
8.7 Thiophene Rings
Thiophene rings comprise another functionality that is easily activated to elec-trophilic species. Thiophene itself is metabolized to the S-oxide, which is viewed as the key primary reactive intermediate. Nucleophilic groups such as thiols react at position 2 of the thiophene S-oxide via a Michael-type addition [23]. Tielinic acid (Figure 8.23) is oxidized to an S-oxide metabolite [24], creating two electron-withdrawing substituents on C2 and a resultant strongly electrophilic carbon at C5 of the thiophene ring [24]. This highly reactive metabolite covalently binds to the enzyme metabolizing it (CYP2C9), triggering an autoimmune reaction resulting in hepatitis. Rotation of the thiophene ring leads to a compound in which the sulphoxide is less reactive and [24] can create a less reactive sulphoxide metabolite which reacts primarily at C2 with nucleophiles. This metabolite is stable enough to escape the enzyme and alkylate other proteins leading to direct toxicity.
Fig. 8.23 Structure of tienilic acid (A) and an isomeric variant (B) which cause hepatotoxicity by autoimmune and direct mechanisms respectively, following conversion to sulphoxide metabolites and resultant electrophilic carbon atoms.
The thiophene ring has also been incorporated into a number of drugs which have diverse toxicities associated with them (Figure 8.24). Ticlopidine, a platelet function inhibitor, is associated with agranulocytosis in patients [25]. Suprofen, a non-
O Cl
О Cl
ring and associated with diverse toxicities Ticlopidine jn patients.
8.8 Thioureas 113
steroidal anti-inflammatory agent has been withdrawn from the market due to acute renal injury [26].
The association of ticlopidine with agranulocytosis has been further investigated [27]. A general hypothesis for white blood cell toxicity is the activation of the drug to a reactive metabolite by HOCl, the principal oxidant being generated by activated neutrophils and monocytes (as in Section 8.4). Under these types of oxidation conditions ticlodipine is activated to a thiophene-S-chloride (Figure 8.25) which reacts further to form other products including a glutathione conjugate.
Fig. 8.25 Metabolism of ticlopidine by white blood cells to the reactive thiophene-S-chloride (A) and further breakdown products of this reactive metabolite.
Tenidap (Figure 8.26) is a dual cyclooxygenase (COX) and 5-lipoxygenase (5-LPO) inhibitor developed as an anti-inflammatory agent. Severe abnormalities in hepatic function were reported in Japanese clinical trials [28]. Although the thiophene is not directly implicated in these findings, the ready activation of this system to potential reactive metabolites may be suggestive of the involvement of this function.
Fig. 8.26 Structure of tenidap, a compound containing a thiophene ring and associated with changes in hepatic function.
114 | 8 Toxicity
The thiourea group has been incorporated into a number of drugs. The adverse reactions of such compounds are associated with the thionocarbonyl moiety. The thiono-carbonyl moiety can be metabolized by flavin-containing monooxygenases and cytchrome P450 enzymes to reactive sulphenic, sulphinic and sulphonic acids which can alkylate proteins. The prototype H2 antagonist metiamide [29] incorporated a thiourea group. This compound caused blood dyscrasias in man. Replacement of the thiourea [29] with a cyanimino grouping produced the very successful compound cimetidine (Figure 8.27).
Fig. 8.27 Structures of the thiourea-containing H2 antagonist metiamide, which caused blood dyscrasias in man, and its cyanoimino-containing analogue cimetidine which did not show similar adverse effects.
Chloroquinolines are reactive groupings due to electron-deficient carbon to which the halogen is attached. This carbon is electron-deficient due to the combined electron-withdrawing effects of the chlorine substituent and the quinoline nitrogen. The electrophilic carbon is thus able to react readily with nucleophiles present in the body. The impact of this grouping on a molecule is illustrated by 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (Figure 8.28). In contrast to many related compounds (chromone-carboxylates) lacking the chloroquinoline, 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate is excreted as a
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