Origins of this Project

Because of the alarming situation of malaria worldwide, as well as the advent of Plasmodium spp. resistant to available drugs, and the lack of a vaccine with a broad spectrum of protection, it is necessary to develop new drugs capable of efficiently combating this disease. A class of substances that have shown to be very promising for the development of antimalarial drugs are the marinoquinolines (MQ), which are substances that contain the quinolinic nucleus (a nucleus present in several antimalarial drugs recommended by the WHO), which was initially discovered in 2006 when researchers isolated MQ A (Figure 1 - first MQ to be identified) from the marine bacterium Rapidithrix thailandica, which presented acetylcholinesterase inhibitory activity (IC50 = 4.9 μM).[1] Subsequently, in 2011, new marinoquinoline derivatives (MQ B-F) were isolated from another bacterium, the Ohtaekwangia kribbensis (Figure 1).[2] All natural MQs (A - F) contain the 3H-pyrrolo[2,3-c]quinoline core and, from biological tests, it was demonstrated that all exhibited antiprotozoal activity against P. falciparum K1 (chloroquine-resistant strain), with IC50 values between 1.7 to 15 μM and, in addition, also showed moderate cytotoxic activity against tumor cell lines KB-3-1, MCF-7, L929 and HUVEC with IC50 values from 0.3 to 8.0 μg mL-1.[2] In 2015, five new marinoquinoline derivatives (MQ G-K) were isolated from bacterial strains of the species Catalinimonas alkaloidigena and Mooreia alkaloidigena.[3] The MQ I was active against strains of bacteria CNJ-912 (Pontibacillus sp.),[3] and when evaluating the activity of MQJ and MQK against the strain of P. falciparum K1 (resistant to chloroquine), it was determined that they are active against this strain, with IC50 values of 3.2 and 6.4 μM, respectively.[4]

Figure 1. Structure of MQs A-K. Source: adapted from [2,3].

In this context, the group of Professor Correia's group at the State University of Londrina in Brazil has carried out the synthesis of several marinoquinoline derivatives, obtaining compounds with in vitro inhibitory activity at the nanomolar level against P. falciparum. Among the synthesized derivatives, the most potent substances ever synthesized are shown in Figure 2.

Figure 2. Structures of marinoquinolines 1 and 2.

Additionally, the marinoquinoline nucleus has several biological applications reported in the literature [1–4], which justifies our interest in this class of compounds, making it an excellent starting point for the development of new drugs for the treatment of malaria and other diseases. However, despite the good in vitro activities with the MQ 1, physicochemical and pharmacokinetic profiles have not yet been well explored to obtain a MQ with all the necessary characteristics to become a drug candidate. In addition, the mode of action of marinoquinolines in the fight against malaria is still unknown, and this information is of great importance in the process of discovering new drugs. If the molecular target is known, the planning of new MQs from the target could be carried out with the aid of computational chemistry, making the process much faster and cheaper, having in mind that only the molecules that would best interact with the molecular target would be synthesized, thus discarding molecules that do not interact well, and which would result in less active substances.

Our main objective would be to make modifications to the structure of MQ 1, however, due to complications during the purification stage of this substance to proceed to the following steps, we decided to modify another marinoquinoline already synthesized and evaluated in Professor Correia's group in Brazil (Marinoquinolina 3, Figure 3), which is a marinoquinoline containing the indole nucleus and which has good antimalarial activity.

Figure 3. Structure of marinoquinolines 3.

1. References [1] SANGNOI, Y. et al. Acetylcholinesterase-inhibiting activity of pyrrole derivatives from a novel marine gliding bacterium, Rapidithrix thailandica. Marine drugs, v. 6, n. 4, p. 578–586, 2008. [2] OKANYA, P. W. et al. Marinoquinolines A−F, Pyrroloquinolines from Ohtaekwangia kribbensis (Bacteroidetes). Journal of Natural Products, v. 74, n. 4, p. 603–608, 25 Apr. 2011. [3] CHOI, E. J. et al. Previously Uncultured Marine Bacteria Linked to Novel Alkaloid Production. Chemistry & Biology, v. 22, n. 9, p. 1270–1279, Sep. 2015. [4] BAELEN, G. VAN et al. Structure–activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues. Bioorganic & Medicinal Chemistry, v. 17, n. 20, p. 7209–7217, Oct. 2009.