Synthesis, antimalarial, antileishmanial, antimicrobial, cytotoxicity, and methemoglobin (MetHB) formation activities of new 8-quinolinamines

Abstract

We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties) and in vivo antimalarial activities of two series of 8-quinolinamines. -[4-(4-ethyl-6methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against P. falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices vs. mammalian cells. The most promising analogs (21-24) also displayed potent antimalarial activity in vivo in a P. berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against L. donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21-24, 26-32 and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development.

Primaquine revisited six decades after its discovery

“…Such effect would be similar to what occurs with CQ, i.e., inhibition of heme crystallization through formation of a drug-heme complex, preventing clearance of hemeassociated toxicity from the parasite [166]. These were also presented by Jain et al studies involving several 8AQ compounds obtained by insertion of substituents at the quinolinic ring of PQ [167], where 4-ethyl-5-pentyloxyprimaquine has also displayed promising results [51]. Overall, it seems that insertion of an appropriate substituent at the quinoline's carbon 2 leads to a small improvement in antimalarial activity along with a decrease in general systemic toxicity.…”

“…Some derivatives of PQ, especially 6-desmethyl-8-aminoquinolines, have been generally more active in vitro than the parent drug against macrophage-contained Leishmania [50]. Recently, Kaur et al presented several biological studies focused on 8AQs and confirmed that PQ has leishmanicidal activity in vitro, but with IC 50 values (w20 mg/mL) superior to those of reference drugs in leishmaniasis therapy, such as pentamidine (IC 50 ¼ 1 mg/mL) or amphotericin B (IC 50 ¼ 0.19 mg/mL) [51]. PQ also showed in vitro leishmanicidal properties when encapsulated in liposomes, against parasiteinfected macrophages [52].…”

“…This produced almost 200 PQ derivatives (Tables 2-4) bearing diverse groups in one or more given positions of the ring [6,46,[161][162][163][164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179]. Globally, the most favourable substituent insertions towards anti-malarial activity where those of methyl groups at positions 4 and 2, tert-butyl at position 2, simultaneous insertion of ethyl substituents at positions 2 and 4 and pentyloxy at position 5, as well as insertion at position 5 of alkoxy, fluoro, and 3-or 4-substituted phenoxy groups [51,163]. Many of these compounds present activity comparable or superior to that of PQ both as gametocytocide and schizontocide, as further described below.…”

Peptidomimetic and Organometallic Derivatives of Primaquine Active against Leishmania infantum

“…Primaquine (PQ) (compound 1 in Fig. 1), an antimalarial 8AQ, is known to exhibit activity against visceral leishmaniasis (3,12,13,15,25,29). Since it leads to some adverse side effects and has a lower therapeutic index than those of VL reference drugs, PQ currently has no applicability in the VL clinical setting.…”

Drug Design by Regression Analyses of Newly Synthesized Derivatives of 8-Quinolinol

“…The antibacterial activity of 8-hydroxyquinoline and its derivatives is long-known. The drugs from this group are used as chemotherapeutics in medicine for more than 120 years (9,10,11,21), and in analytical chemistry as chelators (8,12). In previous studies of ours, some newly synthesized derivatives of 8-Quinolinol were shown to exhibit a higher microbiological activity (4,5,15).…”