2-Aryl-8-aza-3-deazaadenosine analogues of 5′-O-[N-(salicyl)sulfamoyl]adenosine: Nucleoside antibiotics that block siderophore biosynthesis in Mycobacterium tuberculosis

Abstract

A series of 5’-O-[N-(salicyl)sulfamoyl]-2-aryl-8-aza-3-deazaadenosines were designed to block mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) through inhibition of the essential adenylating enzyme MbtA. The synthesis of the 2-aryl-8-aza-3-deazaadenosine nucleosides featured sequential copper-free palladium-catalyzed Sonogashira coupling of a precursor 4-cyano-5-iodo-1,2,3-triazolonucleoside with terminal alkynes and Minakawa-Matsuda annulation reaction. These modified nucleosides were shown to inhibit MbtA with apparent Ki values ranging from 6.1 to 25 nM and to inhibit Mtb growth under iron-deficient conditions with minimum inhibitory concentrations ranging from 12.5 to >50 μM.

Chemical and Biological Aspects of Nutritional Immunity—Perspectives for New Anti‐Infectives that Target Iron Uptake Systems

“…[43] In contrast to adenosine derivatives,i nhibition of the MbtI-catalyzed reaction of 13 to isochorismate (14)b y transition-state mimics such as 23 was found to be less promising (< 10 %inhibition of MbtI at 100 mm). [44] Bacteria are able to adapt the expression of genes in response to cell density through intercellular communication. The" language" of this communication are small signaling molecules (autoinducers), which are secreted into the surrounding medium.…”

“…In contrast to adenosine derivatives, inhibition of the MbtI‐catalyzed reaction of 13 to isochorismate ( 14 ) by transition‐state mimics such as 23 was found to be less promising (<10 % inhibition of MbtI at 100 μ m ) …”

Synthesis and Biological Evaluation of 1,3-Dideazapurine-Like 7-Amino-5-Hydroxymethyl-Benzimidazole Ribonucleoside Analogues as Aminoacyl-tRNA Synthetase Inhibitors

“…There is a clear precedent in the synthesis and application of deazapurines in medicinal chemistry [ 5 , 27 , 28 ]. Within our research group, Gadakh.…”

Chemische und biologische Aspekte von “Nutritional Immunity” – Perspektiven für neue Antiinfektiva mit Fokus auf bakterielle Eisenaufnahmesysteme

“…[41] Eine inhärente Einschränkung von 17 ist der Abbau über die Bildung eines Cyclonucleosides. [44] 3.3. B.…”

“…[43] Im Gegensatz zu den Adenosinderivaten war die Hemmung der MbtI-katalysierten Reaktion von 13 zum Isochorismat 14 (Abbildung 5) durch Übergangszustandsanaloga wie 23 (Abbildung 7) weniger vielversprechend (< 10 % Hemmung von MbtI bei 100 mm). [44] 3.3. Regulation der Siderophor-Biosynthese über Quorum-Sensing-Systeme…”