Property-based design and synthesis of new chloroquine hybrids via simple incorporation of 2-imino-thiazolidin-4-one or 1h-pyrrol-2, 5-dione fragments on the 4-amino-7-chloroquinoline side chain

Abstract

No presente trabalho realizou-se a síntese de novos N-derivados da 4-amino-7-cloroquinolina modificando seletivamente o grupo amino terminal das N- (7-cloroquinolin-4-il)-alquildiaminas, a base do fármaco cloroquina (CQ) mediante a incorporação de sistemas heterocíclicos da 2-imino-tiazolidin-4-ona e 1H-pirrol-2,5-diona. Esses derivados foram selecionados graças às suas propriedades características, e avaliados mediante crivado virtual empregando as plataformas OSIRIS e Molinspiration. Os derivados quinolínicos assim desenhados e sintetizados poderiam incrementar a atividade antimalárica dos análogos da CQ sem afetar a lipofilia como tem se descrito na literatura, postulando-se como candidatos em posteriores testes biológicos.In the present work, the syntheses of new 4-amino-7-chloroquinoline N-derivatives were performed by selective modification of the side chain amino group of N- (7-chloroquinolin-4-yl) alkyldiamines, basis framework of chloroquine (CQ) drug through the incorporation of heterocyclic 2-imino-thiazolidin-4-one and 1H-pyrrol-2,5-dione systems. These potential activity modulators were selected thanks to their characteristic properties, and evaluated by virtual screening employing the OSIRIS and Molinspirations platforms. Designed and synthesized quinolinic derivatives could increase the antimalarial activity of CQ analogues without affecting the lipophilicity as described in literature, suggesting them as candidates for further biological assessments.

Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: A review

“…Furthermore, when the Cl atom was substituted by H-atom, no marked difference in antimalarial activity (ITG2G1 strain) was observed. In spite of resistance to CQ, previous works (both computational and experimental) have shown that modification of the lateral side chain of CQ results in aminoquinoline derivatives that avoid the CQ resistance mechanism [98][99][100][101]. Aguiar et al [102] compared the antimalarial activity mono (39a) and bisquinoline (39b) derivative of CQ against P. falciparum in-vitro and P. berghei in-vivo (Figure 29).…”

Synthesis, characterization, and antiplasmodial activity of polymer‐incorporated aminoquinolines

“…The FTIR spectrum for N ‐(7‐chloroquinolin‐4‐yl)propane‐1,3‐diamine) exhibited the aromatic CC stretching at 1601 and 1480 cm − 1 , N–H stretching at 3250 cm − 1 , CH 2 stretching at 2870 cm − 1 , N–H bending at 1577 cm − 1 , and C–N stretching at 1138 cm − 1 (Fig. ).…”

Quinoline-Based Hybrid Compounds with Antimalarial Activity

“…Rojas et al prepared hybrid compounds containing 4-aminoquinoline and 2-imino-thiazolidin-4-one or 1 H -pyrrol-2,5-dione moiety. The drug-likeness score was in a range of 0.16 to 0.87 based on Lipinski’s rule of five and comparable to chloroquine with a score of 0.67 [ 94 ]. Kumar et al reported hybrid compounds which obeyed Lipinski’s rule of five which further suggested good oral bioavailability influenced by the flexibility of the compounds [ 95 ].…”