Synthesis and antileishmanial activity of novel benzothiadiazine-1,1-dioxide derivatives

MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom CampusLeishmaniasis claims thousands of lives of the human populace every year. Globally, it infects approximately 12-15 million people annually and estimations have indicated that approximately more than 350 million people are at high risk of being infected (Dubie & Mohammed, 2020:12). Most cases occur in poverty-stricken tropical regions where poor water, adequate sanitation and hygiene (WASH) remain a challenge. Furthermore, it leads to an estimated 2.4 million disability adjusted life years (DALYs) (Charlton et al., 2018:219-236) which influence the increases in depression, anxiety and decreases in the overall quality of life (Tamiru et al., 2019:855). Currently, pentavalent antimonials, amphotericin B, miltefosine, pentamidine and paromomycin are the only drugs available for antileishmanial chemotherapy, since no vaccine has been developed yet. However, the emergence of resistance of several Leishmania species, high costs associated with parenteral administration, and adverse side effects have deemed these medicines less effective, which has led to poor patient compliance. Therefore, this highlights the need for more research studies into the development of novel oral antileishmanial agents. Leishmania parasites successfully colonise human cells through the manipulation of carbonic anhydrase enzymes. These enzymes monitor blood pH through a reversible reaction that increases proton and carbon dioxide concentrations. Carbonic anhydrase enzyme is vital in the Leishmania life cycle because it prevents the creation of an acidic environment, thus inhibiting hydrolytic degradation processes initiated by macrophages. Conversely, hydrochlorothiazide is an orally administered anti-diuretic drug that is classified as a benzothiadiazine-1,1-dioxide derivative. It confers potent antileishmanial activity through the inhibition of carbonic anhydrase, suggesting that benzothiadiazine-1,1-dioxide derivatives are not easily degraded by an acidic environment such as the one in the gastrointestinal tract. As a contribution to leishmaniasis research, this study reports a simple two-step method for the synthesis of benzothiadiazine-1,1-dioxide derivatives via a nucleophilic substitution reaction. All synthesized compounds followed Lipinski’s rule of 5, i.e. molecular weight, lipophilicity, hydrogen donating and accepting potential and aqueous solubility, as predicted on SwissADME, http://www.swissadme.ch. Their druglikeness is increased due to enhanced aqueous solubility, which is indicative of potential increased of bioavailability and gastrointestinal tract absorption. They were screened in vitro against promastigotes of Leishmania donovani strains (1S and 9515) and an L. major strain (IR-173) for antileishmanial activity determination. The synthesized compounds did not outperform the standard drug Amphotericin B (AmB). However, in general, they were nontoxic on Vero cells and possessed antileishmanial activities with inhibitory concentration IC50 values ranging from 7 to 74 μM against 1S; 12 to ˃100 μM against 9515, and 0.20 to 3.5 μM against IR-173 promastigotes. Compounds 1, 2b, 2c and 2d were the most potent against L. donovani 1S, with activity IC50 10. Thus, they were identified as visceral leishmaniasis (VL) antipromastigote hits, which encourages their further intracellular amastigote screening. On the other hand, compounds 2, 2c and 2d possessed nanomolar activities L. major parasite with associated selectivity indices SI > 100. Therefore, they could be identified as anti-cutaneous leishmaniasis (CL) leads that need to be confirmed in amastigote screening of L. major parasite. Compounds 1 and 2 with IC50= 0.2 and 6.5 μM, respectively, stand as anti-promastigote hits which encourages more studies focusing on their development as new antileishmanial agents.Master