{"id":668,"date":"2022-07-26T19:17:39","date_gmt":"2022-07-26T22:17:39","guid":{"rendered":"https:\/\/brazmedchem.org\/2022\/?p=668"},"modified":"2022-07-26T19:17:39","modified_gmt":"2022-07-26T22:17:39","slug":"babu-l-tekwani-ph-d","status":"publish","type":"post","link":"https:\/\/brazmedchem.org\/2022\/babu-l-tekwani-ph-d\/","title":{"rendered":"Babu L. Tekwani, Ph.D."},"content":{"rendered":"<p style=\"text-align: justify;\">Title:<b> Tricyclic endoperoxide dimers as promising leads for development of new drugs for drug-resistant Leishmaniasis*<\/b> <span class=\"Apple-converted-space\">\u00a0<\/span><\/p>\n<p style=\"text-align: justify;\"><b>Abstract:<\/b> Visceral leishmaniasis (VL) caused by protozoan parasite <i>Leishmania donovani<\/i>, is a major global health challenge. This neglected disease is fatal if left untreated. Current choices of therapies available for VL are limited to few toxic drugs. Most of the available drugs are getting ineffective due to low efficacy and emerging drug-resistance. A set of novel tricyclic endoperoxide (artemisinin) dimers were identified with outstanding antileishmanial activities against both promastigote and intracellular amastigotes of <i>L. donovani<\/i>. The parent drug artemisinin showed only moderate activity against leishmania cells. <span class=\"Apple-converted-space\">\u00a0 <\/span>The antileishmanial potencies of some of these dimers are several<span class=\"Apple-converted-space\">\u00a0 <\/span>folds higher as compared to clinically used antileishmanial drugs. These dimers did not show<span class=\"Apple-converted-space\">\u00a0 <\/span>any noticeable cytotoxicity against differentiated THP1 cells (a human acute monocytic leukemia cell line) and<span class=\"Apple-converted-space\">\u00a0 <\/span>Vero cells. The dimer analogs were also active against amphotericin-B resistant <i>L. donovani<\/i> as well as <i>L. major<\/i> and <i>L. tropica<\/i>. Based on their selectivity index (SI), calculated by the ratio of toxicity versus antileishmanial activity, the two most active artemisinin dimers namely, dimer-morpholine (IC<sub>50<\/sub> 7 nM, SI &gt;2052), and dimer- GABA (IC<sub>50<\/sub> 13 nM, SI &gt;1086) were selected as promising leads for extended evaluation. Further, the mode of their leishmanicidal action was evaluated by flow cytometric annexin V binding-propodium iodide staining assay.<span class=\"Apple-converted-space\">\u00a0 <\/span>Treatment with dimer-morpholine and dimer-GABA resulted into a time-dependent induction of apoptosis in <i>L. donovani<\/i> promastigotes. While, the parent drug artemisinin, showed only moderate antileishmanial activity and did not produce any apoptotic effect on <i>L. donovani<\/i> cells up to 50 \u00b5M concentration. The antileishmanial activity of the selected set of dimers was reconfirmed against intracellular <i>L. donovani<\/i> amastigotes with SYBR green fluorescent-image analysis assay and also against transgenic luciferase expressing <i>L. donovani<\/i> cells<i>. In vivo<\/i> pharmacokinetic studies in mice with a dimer oxime analog showed significant oral bioavailability (~20%) and metabolic stability. These dimer analogs represent a novel class of antileishmanial drug leads for further preclinical development. *(Supported by National Institute of Allergy and Infectious Diseases, National Institute of Health USA-1R21AI146729-01A1).<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Title: Tricyclic endoperoxide dimers as promising leads for development of new drugs for drug-resistant Leishmaniasis* \u00a0 Abstract: Visceral leishmaniasis (VL) caused by protozoan parasite Leishmania donovani, is a major global health challenge. This neglected disease is fatal if left untreated. Current choices of therapies available for VL are limited to few toxic drugs. Most of&hellip;<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"post_series":[],"class_list":["post-668","post","type-post","status-publish","format-standard","hentry","category-sem-categoria","entry","no-media"],"_links":{"self":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts\/668","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/comments?post=668"}],"version-history":[{"count":1,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts\/668\/revisions"}],"predecessor-version":[{"id":669,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts\/668\/revisions\/669"}],"wp:attachment":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/media?parent=668"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/categories?post=668"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/tags?post=668"},{"taxonomy":"post_series","embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/post_series?post=668"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}