Cutaneous Leishmaniasis (CL) caused by L. braziliensis presents as several clinical forms, which range from a localized ulcerated lesion to disfiguring lesions in mucosal areas. L. braziliensis can also cause disseminated leishmaniasis, a severe form of disease that frequently presents with mucosal involvement. CL affects 1.5 million people worldwide, and the current first line treatment are pentavalent antimony compounds that present toxicity and are subject to parasite resistance, making it evident the need for better therapeutical options. One of the challenges in the development of novel antileishmanial compounds is achieving potent activity against the intracellular stage of the parasite, the stage present in the mammalian host, without harming the host cell. Previously, we identified a compound series that displayed effective antiparasitic activity against L. braziliensis. Herein, we explored these compounds and evaluated their effectiveness employing murine macrophages, followed up by experiments in vivo. Macrophages infected with L. braziliensis and exposed to the compound series in a dose dependent manner showed that molecules Cpd1 and Cpd2 reduced the percentage of infected cells and the number of intracellular amastigotes in a significant manner. Similar results were obtained upon infection with L. major and both compounds also did not exhibit cellular toxicity. Parasite killing was accompanied by an increase in the production of TNF and superoxide and both molecules are associated macrophage effector functions. Lastly, in a pre-clinical mouse model of CL caused by L. braziliensis, we observed that topical application of Cpd1, in gel- based form employing bacterial cellulose, impaired lesion development and significantly reduced parasite burden. These results indicate that this compound series can be further explored for the development of novel chemotherapeutic alternatives for CL caused by L. braziliensis, the causative agent of localized, mucosal and disseminated leishmaniasis.