Development of a synthetic route towards N4,N9-disubstituted 4,9-diaminoacridines: On the way to multi-stage antimalarials

4,9‐Diaminoacridines and 4‐Aminoacridines as Dual‐Stage Antiplasmodial Hits

“…Compounds 1 and 3 – 6 were prepared as previously described, and their structural analyses (Supporting Information) agreed with formerly reported data [10] …”

“…An alternative two‐step (steps viii and vii) procedure, via cleavage of the p ‐TSH moiety in 7 using Na 2 CO 3 in aqueous ethylene glycol to give 9 and subsequent reduction of the latter with hydrazine hydrate and Pd/C to afford 8 , increased the overall yield to 40 %. Aniline 8 was next alkylated with the appropriate N ‐( N ‐bromoalkyl)phthalimide, as previously reported by us [10] . This afforded compounds 10 a – c in moderate yields (30‐60 %), which were quantitatively converted into the respective final 4‐aminoacridines 2 a – c by hydrazinolysis (step iv) using excess hydrazine monohydrate in refluxing tetrahydrofuran (THF).…”

“…In view of the above, we have synthesized 4,9-diaminoacridines 1 a-c and 4-aminoacridines 2 a-c, as depicted in Scheme 1. The synthetic route towards 4,9-diaminoacridines 1 had been previously reported by us, [10] whereas the synthesis of 4-aminoacridines 2 starting from 3, the common precursor to both compounds 1 and 2, was established in the present work, as follows. The first step was the reduction of the nitro group, along with the removal of chlorine in position 9 of the acridine ring in 6,9-dichloro-2-methoxy-4-nitroacridine 3; classical catalytic hydrogenation using H 2 (g) and Pd/C (step v in Scheme 1) did not afford the desired compound, as nonselective removal of the two chlorine atoms occurred (data not shown).…”

“…Aniline 8 was next alkylated with the appropriate N-(N-bromoalkyl)phthalimide, as previously reported by us. [10] This afforded compounds 10 a-c in moderate yields (30-60 %), which were quantitatively converted into the respective final 4-aminoacridines 2 a-c by hydrazinolysis (step iv) using excess hydrazine monohydrate in refluxing tetrahydrofuran (THF). Detailed procedures and relevant spectroscopic data on intermediate and final compounds are given in the Supporting Information.…”

Acridine-Based Antimalarials—From the Very First Synthetic Antimalarial to Recent Developments

“…Recently, Fonte et al developed QN derivatives through the introduction of a like PQ -side chain in position 4 of the acridine ring ( Figure 10 ) towards multi-stage antimalarial drugs [ 21 ]. After the establishment of the synthetic route of these derivatives [ 22 ], the series of three compounds, with different side-chain length, were evaluated for their antimalarial activity against CQS 3D7 and CQR Pf W1 strains, and the hepatic stages of P. berghei . Overall, all the compounds exhibited activity against both stages of the parasite life cycle.…”