Novel Synthetic Approaches for Bisnaphthalimidopropyl (BNIP) Derivatives as Potential Anti-Parasitic Agents for the Treatment of Leishmaniasis

Abstract

Leishmaniasis is a neglected parasitic disease that is widely seen in more than 60 countries worldwide, including Turkey and its subcontinental region. There are several chemotherapy agents for the treatment of leishmaniasis, including pentavalent antimonials—i.e., sodium stibogluconate (Pentostan) and meglumine antimoniate (Glucantim), pentamidine, conventional amphotericin B deoxycholate, miltefosine, paramomycin (aminosidine), and liposomal amphotericin B. However, these therapies are usually unsatisfactory due to dose-limiting toxicity issues and limited efficacy. Furthermore, resistance gained by parasites endangers future success of these therapies. Addressing these issues, the development of novel drugs with high efficacy has a vital importance. Latest studies have shown that bisnaphthalimidopropyl (BNIP) derivatives display high activity against Leishmaniasis parasites by selectively targeting parasitic sirtuin proteins and interacting with DNA. Despite the promising anti-parasitic activity, the low solubility and toxicity on human macrophages are the limitations to overcome. This study describes the new synthesis strategies for existing—i.e., BNIPDaoct and BNIPDanon—and novel BNIP derivatives differing in respect of their alkyl linker chain lengths. The new synthesis approach provides certain advantages compared to its existing alternatives reported in the literature. The proposed methodology does not only decrease the number of synthesis steps and production time of BNIPDaoct and BNIPDanon, but also provides higher yields, thereby making the synthesis highly cost-effective.

Antileishmanial Activity of BNIPDaoct- and BNIPDanon-loaded Emulsomes on Leishmania infantum Parasites

“…Synthesis of BNIP derivatives were accomplished as described by Keskin and others (Keskin et al, 2019). Accordingly, the synthesis involves two-step reactions.…”

“…In the second step, the intermediate compound (508 mg, 2 mmol) and 1,8-dibromoctane (272 mg, 1 mmol) were let into reaction in the presence of DBU base (152 mg, 1 mmol) in methanol to produce BNIPDaoct. The two-step BNIPDaoct synthesis was achieved overall with 48% yield (Keskin et al, 2019).…”

“…For the synthesis of BNIPDanon, the intermediate compound (508 mg, 2 mmol) was let into reaction with DIEA (259 mg, 2 mmol), and 1,9-dibromononane (286 mg, 1 mmol) were added to in toluene/ethanol (1:1) (60 ml) and then were followed by reflux for 48 h. BNIPDanon synthesis was achieved overall with 50% yield (Keskin et al, 2019).…”

“…In all synthetic methods, appropriate reference methods were used. LC-MS and NMR data of the synthesis products and intermediate compounds are available in the previously published study of Keskin et al (2019).…”

The Current Directions of Searching for Antiparasitic Drugs

“…As a result, compounds with better solubility and antiparasitic activity were obtained. Currently, BNIP derivatives are being tested for antiprotozoal activity against Leishmania infantum [ 49 ].…”