Discovery of Novel 7-Aryl 7-Deazapurine 3′-Deoxy-ribofuranosyl Nucleosides with Potent Activity against Trypanosoma cruzi

Abstract

Chagas disease, the leading cause of cardiac-related mortality in endemic Latin American countries.Trypanosoma cruzi, the disease-causing pathogen, is unable to synthesize purines de novo, necessitating salvage of pre-formed host purines. Therefore, purine and purine nucleoside analogs might constitute an attractive source to identify antitrypanosomal hits. In this study, structural elements of two purine nucleoside analogs, i.e. cordycepin and a recently discovered 7-substituted 7-deazaadenosine led to the identification of novel nucleoside analogs with potent in vitro activity. The structure-activity relationship of substituents at C7 was investigated, ultimately leading to the selection of compound 5 having a C7 para-chlorophenyl group for in vivo evaluation. This derivative showed complete suppression of T. cruzi Y-strain blood parasitemia when orally administered twice daily for 5 days at 25 mg/kg and was able to protect infected mice from parasite-induced mortality. However, sterile cure by immunosuppression could not be demonstrated. improved efficacy and safety profiles and preferentially with a new mode-of-action should be pursued. 4 Recently, several reports on new lead molecules have been published, marking a renewed hope in finding drugs to treat Chagas disease. [6][7][8][9][10] Trypanosoma cruzi, like their related T. brucei counterparts, are purine auxotrophs, i.e. they rely on the salvage of pre-formed purine analogs from the host as they are unable to synthesize the purine ring themselves. [11][12][13][14] Hence, focused purine (nucleoside) libraries are a promising source for discovering new antitrypanosomal agents. Natural antibiotics such as tubercidin, 15 Formycin A 16 and Formycin B, [17][18][19] cordycepin, [19][20][21][22][23] stylomycin aminonucleoside (also known as puromycin aminonucleoside) [24][25] as well as allopurinol [26][27] and certain other inosine analogs 20,[28][29] have been found to possess activity against T. cruzi (Figure 1). Allopurinol, although not a nucleoside analog sensu stricto (its active metabolite is generated by phosphoribosylation in the parasite 26 ), has been evaluated in clinical trials. 30 Figure 1: Examples of purine (nucleoside) analogs active against T. cruzi.Our group recently revisited the natural nucleoside antibiotic tubercidin and a series of 7-substituted analogs [in the body of the text, purine numbering will be used for nucleoside analogs; however, in the experimental section, IUPAC nomenclature and numbering of the pyrrolo[2,3-d]pyrimidine system will be applied] in search of novel hits active against T. brucei spp. parasites. 31 This study indicated that certain phenyl-substituted analogs (e.g. 2) also showed promising in vitro activity against intracellular T. cruzi amastigotes, which motivated us to explore related 7-substituted 7-deazapurine moieties with the carbohydrate group of cordycepin, i.e. a 3'-deoxy-D-ribofuranose for their activity against T. cruzi.Related sugar-modified 7-deazapurine nucleosides 32-34 have previously been assayed ...

C6–O-alkylated 7-deazainosine nucleoside analogues: Discovery of potent and selective anti-sleeping sickness agents

“…Finally, we investigated the effects of removing the hydroxyl group at the 3'-position of the sugar moiety, a strategy that in the 7-deazaadenosine series led to a significant increase in antitrypanosomal activity. 20,39 3'-Deoxyinosine 23 41 was confirmed to elicit low micromolar activity against T. brucei (Table 3). In the case of 7-deazainosine (7), however, 3'-deoxygenation (i.e.…”

“…Unless otherwise specified, they were used as received. Nucleoside derivatives 5 20 , 47 34 , 48 34 , 49 34 , 50 34 and 62 39 were prepared according to published procedures. Moisture sensitive reactions were performed under either argon or nitrogen atmosphere.…”

Review on Experimental Treatment Strategies Against Trypanosoma cruzi

“…[ 106,107] Xanthine analogs Xanthine analogs showed in vitro activity and were able to reduce parasitemia in CL-infected mice. mice; the drug reduced hepatic and cardiac lesions and prevented electrocardiographic abnormalities induced by the parasite infection.…”

Antiparasitic and Cytotoxic Activity of Bokkosin, A Novel Diterpene-Substituted Chromanyl Benzoquinone From Calliandra portoricensis

“…The closely related genes LmexNT1.1 and LmexNT1.2 transport adenosine, thymidine, and uridine (Alzahrani et al, 2017;Campagnaro and De Koning, 2020) as well as a number of purine and pyrimidine nucleoside analogs with strong antileishmanial activity, including the antibiotic tubercidin (Vasudevan et al, 1998;Aoki et al, 2009), and 5-F-2 ′ -deoxyuridine (Alzahrani et al, 2017). Since these genes are functionally highly conserved in Leishmania species (Alzahrani et al, 2017) and tubercidin analogs have recently been reported to have excellent antikinetoplastid activity in vitro and in vivo (Hulpia et al, 2018(Hulpia et al, , 2019aLin et al, 2019) this strain was included here as a further control. The knockout strategy for the NT1.1/NT1.2 allele in L. mexicana cas9 was performed as described previously (Beneke et al, 2017).…”

“…Nature has been a rich source of biologically active compounds for the development of new pharmacological agents themselves or from which active compounds have been derived using their novel structures as a template, over the past decades (Cragg and Newman, 2005;Newman and Cragg, 2020). Several compounds isolated from natural sources have been shown to inhibit the growth of trypanosomes in vitro and in vivo, e.g., cordycepin and its chemical analogs (Vodnala et al, 2013;Hulpia et al, 2018Hulpia et al, , 2019a, isolated from the fungus Cordyceps militaris, and quercetin and its derivatives, which is a polyphenolic flavonoid commonly found in plants (Mamani-Matsuda et al, 2004). Other examples include the trypanocidal activity of two dipeptide compounds isolated from the roots of Zapoteca portoricensis (Nwodo et al, 2014), a clerodane-type diterpenoid isolated from Polyalthia longifolia (Ebiloma et al, 2018a), steroid alkaloids from Holarrhena africana (Nnadi et al, 2019) and the anti-kinetoplastid properties of propolis (Alotaibi et al, 2019;Siheri et al, 2019).…”