Considerations about the structure—activity relationships of 8-aminoquinoline antimalarial drugs

Bulletin of the World Health Organization, 59 (3): 459-462 (1981) Considerations about the structure-activity relationships of 8-aminoquinoline antimalarial drugs JAMES D. MCCHESNEY1 A discussion of the structure-activity relationships (SAR) of 8-aminoquinoline antimalarial drugs is presented. Consideration is given to the potential role of metabolic transformations in the in vivo activation of 8-aminoquinolines. It is emphasized that the mechanism ofaction of8-aminoquinoline agents has not yet been established and thus any analysis ofSAR must be speculative. The discovery of synthetic antimalarial agents is generally believed to stem from early observations that methylene blue seemed to have chemotherapeutic effects on malaria patients. Observations that substi- tution of one of the methyl groups of methylene blue by a dialkyl aminoalkyl side-chain produced increased activity, and that 8-aminoquinoline had schizonto- cidal activity, led to the development of the first synthetic antimalarial drug, pamaquine, by German chemists in the 1920s. The early discovery of the 8-aminoquinolines and the demonstration of their activity against many stages of the plasmodial life cycle have meant that they have been thoroughly investigated as antimalarial agents. Reviews of the early studies can be found elsewhere (1-3). However, early assessments were based on blood schizontocidal activity, whereas the 8-aminoquinolines are also potent tissue schizontocides. The recent development of the Plasmodium cynomolgi screen in rhesus monkeys has provided a means of measuring this action, but the procedure is not suitable as a primary screen. Thus, much of the early data on 8-amino- quinolines may need to be reassessed before any conclusions can be drawn about their structure- activity relationships (SAR) with respect to tissue schizontocidal action. STRUCTURE-ACTIVITY RELATIONSHIPS The quinoline nucleus The presence of a quinoline ring in quinine, coupled with the observation of schizontocidal activity in 8-aminoquinolines, has led to the inclusion of the quinoline nucleus in the majority ofcompounds tested for antimalarial activity. However, the quinoline I Professor and Chairman, Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, MS 38677, USA. nucleus is not indispensable, and certain amino- alcohols containing phenanthrene, anthracene, or naphthalene rings have been shown to have significant blood schizontocidal activity. The tissue schizon- tocidal activity of these compounds has recently been tested by Archer and co-workers (4). They prepared the naphthalene analogues of the 5,6-dimethoxy-8- aminoquinolines, corresponding to pamaquine, primaquine, and quinocide. Archer also reported pre- paration of the isoquinoline and cinnoline analogues of pamaquine, but gave no details. All the pamaquine analogues proved to be inactive. The dimethoxynaph- thalene analogues of primaquine and quinocide were either inactive or toxic according to the dose given. Interestingly, a primaquine analogue homologue, 1 ,2-dimethoxy-4-[(4-amino- 1 -ethylbutyl)aminoJ- naphthalene, showed some activity albeit at levels close to the toxic dose. The fact that two of the seven analogues containing a naphthalene ring had anti- malarial activity suggests that the quinoline nucleus is not essential for tissue schizontocidal activity. Carroll and co-workers (5) have investigated substitution of the 8-aminoquinoline ring with various reduced quinoline ring analogues. They prepared 1-alkyl-1,2,3,4-tetrahydroquinoline, 1-alkyl-1,2-di- hydroquinoline, and 2-substituted 8-methoxy-5, 6-dihydro-4-imidazo[i,j]quinoline analogues. None showed any significant antimalarial activity in the mouse screen. Some 1-methyl-1,2-dihydroquinoline analogues of primaquine showed low suppressant activity in the P. cynomolgi screen in rhesus monkeys. Klayman and co-workers have examined the substi- tution of the quinoline ring with an acridine moiety (6). The results of the tissue schizontocidal test indicate that the activity of these compounds is low compared with that of primaquine. Ring-substituted derivatives The effect of adding substituents to the quinoline nucleus of the 8-aminoquinolines is a function of the 4075 - 459 J. D. McCHESNEY position and the nature of the substituent. Since the presence of a 6-oxygen function has been shown to enhance activity, nearly all recent work on SAR has retained the 6-methoxy group of primaquine and explored the additional effect of further substituents. 2-Substituted analogues. Blanton and co-workers (7) have examined primaquine analogues with 2-substituents including benzyloxy, substituted benzyloxy, benzylthio, methoxy, amino, alkylamino, acetamido, chloro, alkyl, and vinyl radicals. Some of these analogues, notably the benzyloxy and certain substituted benzyloxy derivatives, were active as radical curatives. They were less active and less toxic than primaquine. Additionally, the 2-ethyl derivative of primaquine exhibited significant antileishmanial activity. However, it was considered that the activity patterns seen did not justify further testing. 3-Substituted analogues. Substituents at position 3 tend generally to lower activity and toxicity (1). With some radicals, e.g., phenyl, the toxicity is reduced more than the activity, although not enough to make it a better antimalarial agent. 4-Substituted analogues. The preparation of 4-substituted 8-aminoquinolines has been more rewarding. LaMontagne et al. (8) and Carroll et al. (9) have reported preparation of a variety of 4-substituted derivatives. Their work was based upon observations that 4-methylprimaquine was approximately twice as active and rather less toxic than primaquine itself (10). Of the numerous prepared derivatives, only those with lower alkyl (methyl and ethyl) and vinyl substituents showed radical curative activity, which was approx- imately equal to or slightly greater than that of primaquine. These agents are of particular interest because they are significantly less toxic than prima- quine. Additionally, 4-methylprimaquine has been shown to possess significant activity against Trypano- soma cruzi (11). 5-Substituted analogues. Early observations showed that 5-oxygenated 8-aminoquinolines retained potent activity, often with reduced toxicity. Following up on these observations, Nodiff and co- workers (12, 13) have demonstrated that primaquine's toxicity can be reduced by the introduction of phenylthio, anilino, or phenoxy groups at position 5. The phenoxy and substituted phenoxy derivatives retained the highest level of tissue schizontocidal activity. 6-Substituted analogues. Early work on the preparation of 8-aminoquinoline antimalarial agents demonstrated that the presence at position 6 of an oxygen function, e.g., hydroxyl, methoxyl, (3- hydroxyethoxyl, increased antimalarial activity but also increased toxicity. In practice, all 8-aminoquino- line antimalarial analogues contain a methoxyl group at position 6, since these are the most readily prepared derivatives. 7-Substituted analogues. Introduction of groups at position 7 of the quinoline ring generally leads to loss of activity (1). Multi-position ring-substituted derivatives. The effect of three substituents on the 8-aminoquinoline ring has been examined in a few cases. Carroll et al. (14) found that 2,4-dialkyl-6-methoxy-8-amino- quinoline analogues were less active than primaquine both in the mouse blood schizontocidal and monkey tissue schizontocidal screens. The bromodimethoxy- naphthalene analogue was found by Archer et al. (4) to be more active and less toxic than the simpler dimethoxynaphthalene derivative. This material is most closely analogous to 2-bromo-5-methoxyprima- quine. Burghard & Blanton (15) have recently reported that 4-methyl-5-fluoroprimaquine showed very high activity but was also very toxic. This suggests that more extensive examination of 4,5-disubstituted primaquine analogues is warranted. 8-Amino substituents. The nature of the amino side-chain at position 8 has been extensively investi- gated (1). Optimal activity was obtained with 2-6 methylene groups between the two nitrogens of the side-chain. Homologues with an even number of methylene groups were found to be slightly less active than those with an odd number. The introduction of additional heteroatoms into the basic side-chain did not improve the activity of the compounds. Anti- malarial activity is only found in those compounds where the 8-amino group is secondary. It should be noted that these results are mainly from blood schizontocidal screens and may need re-evaluation in the tissue schizontocidal system. The optical antipodes of primaquine have been tested for prophylactic antimalarial activity against P. cynomolgi in rhesus monkeys (16, 17). The radical curative activities of (+ )- and (-)-primaquine were essentially identical and were similar to that of racemic primaquine. However, (-)-primaquine was 3-5 times more toxic than (+ )-primaquine and about twice as toxic as racemic primaquine in rhesus monkeys. A critical comparison of ( + )- and racemic primaquine in human volunteers is needed. As pointed out by Sweeny& Strube (3), the data on which the above discussion is based were gathered partly from blood schizontocidal screens, whereas the major value of the 8-aminoquinolines is their tissue schizontocidal activity. In addition, Greenberg et al. (18) have presented strong evidence that the 8-amino- quinoline antimalarials are not active directly but must undergo transformation to active metabolites. AAA STRUCTURE-ACTIVITY RELATIONSHIPS OF 8-AMINOQUINOLINES There is some evidence that these active metabolites are 5,6-dihydroxy-8-aminoquinolines, which presum- ably function as oxidation-reduction substrates, and disrupt sensitive biological oxidation-reduction pathways or systems. A similar mechanism may be responsible for the toxicity of these agents, which results in haemolysis of erythrocytes deficient in glucose-6-phosphate dehydrogenase. The fact that the 5-oxygenated primaquine analogues are highly active lends support to this hypothesis. However, until the mechanism of action of 8-aminoquinolines is eluci- dated, a thorough understanding of the SAR of this class of antimalarial agents will not be possible. R-SUMt CONSIDERATIONS SUR LES RELATIONS STRUCTURE-ACTIVITE DES ANTIPALUDIQUES DERIVkS DE L'AMINO-8 QUINOL-INE On estime generalement que la decouverte des antipalu- diques de synthese decoule d'observations anciennes d'apres lesquelles le bleu de methylene semblait avoir des effets chimiotherapiques sur les malades impaludes. Du fait de la decouverte precoce de l'activite des amino-8 quinoleines contre plusieurs stades du cycle biologique des plasmo- diums, ces composes sont parmi les agents antipaludiques etudies le plus A fond en ce qui concerne la relation struc- ture-activite (RSA). La substitution au noyau quinolene de I'amino-8 quino- line de differents systemes cycliques, notamment naph- talene, isoquinoleine, cinnoline et acridine, n'a pas donne de composes ayant une activite accrue ou une toxicite moindre. De meme, la substitution au noyau quinoleine de diverses quinoltines reduites a donne des composes qui ne manifestaient pas d'activite antipaludique importante dans les epreuves de selection sur la souris. Neanmoins, certains analogues methyl-l dihydro-l ,2 quinoleine de la primaquine presentaient une faible activite suppressive dans l'epreuve sur P. cynomolgi chez le singe rhesus. L'addition de substituants au noyau quinoleine a, sur l'activite, un effet qui est fonction de la position et de la nature de substituant. L'evaluation de divers analogues substituts en position 2 n'a pas rtvtlt de composts douts d'une activite suffisante pour justifier des epreuves plus etendues ni une extension de cette serie. Les substituants en position 3 tendent a abaisser l'activite et la toxicite. Cependant, il n'a pas ett signalt d'analogue qui soit suptrieur a la primaquine. La preparation d'aminoquino- leines substitutes en position 4 a ett un peu plus satis- faisante. Les premiers membres des stries alcoyle (methyle et ethyle) et vinyle prtsentent une activitt curative radicale A peu pres egale A celle de la primaquine ou legerement supe- rieure. Ces agents sont inttressants car leur toxicite est nette- ment plus basse. Des premitres observations ont montre que les aminoquinoleines oxygen6es en position 5 conservent une grande activite s'accompagnant souvent d'une toxicite reduite. Dans cette serie, les composes conservant la meilleure activite schizonticide tissulaire font partie des derives phenoxy et phenoxy substitues. Essentiellement, tous les analogues des amino-8 quinoleines examines jusqu'ici avaient un groupement methoxyle en position 6, ce qui accroit nettement l'activite par comparaison avec le produit non substitue. L'introduction de groupements en position 7 du noyau quinoleine conduit a une perte d'acti- vite. La presence de multiples substituants sur le cycle amino-8 quinoleine a e etudiee dans un petit nombre de cas. Singulierement, I'analogue methyl-4 fluoro-5 prima- quine presentait une activite tres elevee, mais etait egalement tres toxique. La nature de la chaine laterale aminee en position 8 a ete le caractee structural le plus etudie. Les r6sultats ainsi obtenus ont ete suffisamment passes en revue dans d'autres publica- tions. Recemment, un rapport a signale la resolution de la primaquine en ses antipodes optiques. Ce qui est d'impor- tance potentielle, c'est que l'activit6 curative radicale des deux antipodes est essentiellement egale et la meme que celle de la primaquine racemique, mais l'antipode (-) est trois a cinq fois plus toxique que l'antipode ( + ) et a peu pres deux fois plus toxique que le melange racemique pour le singe rhesus. II est evident que cette observation doit etre verifi6e chez l'homme. Une pleine comprehension de la relation structure-acti- vite de cette classe d'antipaludiques ne sera possible que lorsque le m&anisme d'action des amino-8 quinoleines sera evalue. Le metabolisme de cet agent semblant jouer un r6le crucial dans son activite biologique, il est imperatif de proceder A des recherches sur le metabolisme des amino-8 quinoleines. REFERENCES 1. THOMPSON, P. E. & WERBEL, L. M. Antimalarial agents. New York, Academic Press, 1972, pp. 100-122. 2. ROLLO, I. M. Drugs used in chemotherapy of malaria. In: Goodman, L. 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