2-Aminooxazole as a Novel Privileged Scaffold in Antitubercular Medicinal Chemistry

Abstract

To obtain effective eradication of numerous infectious diseases such as tuberculosis, it is important to supply the medicinal chemistry arsenal with novel chemical agents. Isosterism and bioisosterism are widely known concepts in the field of early drug discovery, and in several cases, rational isosteric replacements have contributed to improved efficacy and physicochemical characteristics throughout the hit-to-lead optimization process. However, sometimes the synthesis of isosteres might not be as straightforward as that of the parent compounds, and therefore, novel synthetic strategies must be elaborated. In this regard, we herein report the evaluation of a series of N-substituted 4-phenyl-2aminooxazoles that, despite being isosteres of a widely used nucleus such as the 2-aminothiazole, have been only seldom explored. After elaboration of a convenient synthetic strategy, a small set of 2-aminothiazoles and their 2-aminooxazole counterparts were compared with regard to antitubercular activity and physicochemical characteristics.

Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole

“…Non-substituted 2-AMO/2-AMT used for subtype I compounds were obtained from commercial sources and used without further purification. The 2-AMO/2-AMT fragment of subtype II (4-phenyl-substituted 2-AMO/2-AMT) was prepared by reacting 2-bromoketone with thiourea (method a [ 9 ] in Figure 2 ) or urea (method b [ 8 ]) as described before. For the final coupling, we have investigated several procedures, including coupling reagents such as 1,1′-carbonyldiimidazole (CDI).…”

“…Among five-membered heterocycles, thiazole, and especially 2-aminothiazole (2-AMT), has a privileged position in antimicrobial research and is contained in many highly active compounds [ 8 , 9 , 10 , 11 ]. Several successful marketed drugs can already be identified as bearing the 2-AMT fragment, e.g., aztreonam or the whole 3rd generation of cephalosporins, where the 2-AMT fragment is a determining sign (e.g., cefotaxime).…”

“…Isosteric replacement of 2-AMT with 2-aminooxazole (2-AMO) is a common medicinal chemistry practice [ 16 ], but it does not seem to be as extensively established in the design of antimicrobials. Recently, Azzali and colleagues [ 8 ] have pointed out that 2-AMO could potentially alleviate at least some of the often-observed negatives of 2-AMT (described above) and showed that the 2-AMO isosteres behaved correspondingly to their 2-AMT counterparts in terms of antimicrobial activity, while not presenting any significant cytotoxicity or PAINS-like behavior. Even though Azzali et al investigated this substitution in the context of antimycobacterial agents, we see no apparent reason why it could not also be translated to other antimicrobial areas as already seen in the literature, e.g., in references [ 17 , 18 ].…”

“…In some derivatives, the issues with low solubility led to the inability to carry on with antibacterial evaluations, e.g., by Zitko and colleagues [ 11 ]. Inspired by the results of Azzali et al [ 8 ], we decided to test the hypothesis of improvement of physico-chemical properties while retaining antimicrobial activities for the 2-AMT -> 2-AMO isosteres. Title compounds were designed as a pivotal series of heteroaromatic derivatives of the general structure presented in Figure 1 based on the known antimicrobial (antibacterial and antimycobacterial) agents and FabH inhibitors, especially acyl derivatives described by Zitko and colleagues [ 11 ] (structure A in Figure 1 ), Meissner and colleagues [ 21 ] (structure B ), and Li and colleagues [ 9 ] (structure C ).…”

Discovery of Substituted (2-Aminooxazol-4-yl)Isoxazole-3-carboxylic Acids as Inhibitors of Bacterial Serine Acetyltransferase in the Quest for Novel Potential Antibacterial Adjuvants

“…Inspired by these preliminary findings, in the second step synthetic efforts were devoted toward the synthesis of further analogues. In particular, a small set of analogues of the 2-aminooxazole derivatives 18 and 19 was designed and synthesised, taking advantage from a synthetic protocol that we have previously reported [ 40 ], which proved to be particularly versatile in the case of substituted 2-aminooxazoles ( Scheme 1 ). The small set of derivatives consisted of 3-carboxylisoxazoles characterised by the presence of variously substituted aromatic and heteroaromatic rings attached at the nitrogen of the 2-aminooxazole ( 21a – e , 22a – e ).…”