Collaborative virtual screening to elaborate an imidazo[1,2-a]pyridine hit series for visceral leishmaniasis

Abstract

Ligand-based similarity screening of proprietary pharmaceutical company libraries enables rapid hit to lead investigation of a chemotype with anti-leishmania activity.

Synthesis and Antimicrobial Evaluation of 2-(6-Imidazo[1,2-a]pyridin-2-yl-5-methyl-2,4-dioxo-3-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)-N-arylacetamide Derivatives

“…As a part of our research on struction of 6-heteryl-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-diones, we stu interaction of the readily synthetically available 6-(bromoacetyl)-5-methyl-3-p eno[2,3-d]pyrimidine-2,4(1H,3H)-dione 1 [3] with 2-aminopyridine. We tried a Several imidazo[1,2-a]pyridine derivatives were reported as compounds with antimicrobial properties which may be useful against parasites of the Leishmania genus (VII) (Figure 2) [9]; this heterocyclic system is the core structure of savolitinib [10], a mesenchymal epithelial transition factor (MET) inhibitor recently approved in China after the results of a pivotal phase II trial in patients with NSCLC/pulmonary sarcomatoid carcinoma [11]. This fragment is also a part of the innovative drug olprinone, which is a selective phosphodiesterase 3 (PDE3) inhibitor [12].…”

“…thiothieno [2,3-d]pyrimidines, which can possibly act as inhibitors of bacterial T (Figure 1) [8]. Several imidazo [1,2-a]pyridine derivatives were reported as compounds w microbial properties which may be useful against parasites of the Leishmania ge (Figure 2) [9]; this heterocyclic system is the core structure of savolitinib [10], a m mal epithelial transition factor (MET) inhibitor recently approved in China afte sults of a pivotal phase II trial in patients with NSCLC/pulmonary sarcomatoid ca [11]. This fragment is also a part of the innovative drug olprinone, which is a phosphodiesterase 3 (PDE3) inhibitor [12].…”

Current leishmaniasis drug discovery

“…77 In addition to the compounds found in clinical trials and the recent efforts to obtain new chemical entities able to overcome the issues related to the current treatment, such as toxicity, adverse effects, and advent of resistance, many synthesized agents, natural drugs or semisynthetic derivatives have been reported with remarkable antileishmanial activities, offering great potential for the future development of new antileishmanial chemotherapeutic drugs. [79][80][81][82][83][84][85][86][87][88][89] As most of the above cited studies indicate, the main strategy used to obtain currently available drugs is known as the phenotypic approach, when a new drug prototype is obtained without any knowledge about its target or specific function against the disease. 78 The screening of large libraries of drug candidates to obtain a hit compound and then elaborate their mechanisms of action has been successful in drug discovery but delays the progress to find the best possible prototype for that specific target.…”

“…In addition to the compounds found in clinical trials and the recent efforts to obtain new chemical entities able to overcome the issues related to the current treatment, such as toxicity, adverse effects, and advent of resistance, many synthesized agents, natural drugs or semisynthetic derivatives have been reported with remarkable antileishmanial activities, offering great potential for the future development of new antileishmanial chemotherapeutic drugs. 79–89…”

Filarial nematode phenotypic screening cascade to identify compounds with anti-parasitic activity for drug discovery optimization

“…Available phenotypic assays have relatively low throughput; therefore, ranking, and triaging molecules prior to characterization through these different assays is essential. Utilizing the heritage Celgene Global Health collection enriched with chemical matter in the neglected disease (NTD) space, compounds were initially identified by their ability to either kill or interrupt the developmental stages of C. elegans ( Subbian et al, 2016 ; Mundhra et al, 2018 ; Tummalapalli et al, 2018 ; Akao et al, 2021 ) . Primary parasitic evaluation showed reduction of motility in Onchocerca nematodes, O. gutturosa and O. lienalis .…”