Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria

Abstract

A series of indolyl-3-methyleneamines incorporating lipophilic side chains were designed through a structural rigidification approach and synthesized for investigation as new chemical entities against Mycobacterium tuberculosis (Mtb). The screening led to the identification of a 6-chloroindole analogue 7j bearing an N-octyl chain and a cycloheptyl moiety, which displayed potent in vitro activity against laboratory and clinical Mtb strains, including a pre-extensively drug-resistant (pre-XDR) isolate. 7j also demonstrated a marked ability to restrict the intracellular growth of Mtb in murine macrophages. Further assays geared toward mechanism of action elucidation have thus far ruled out the involvement of various known promiscuous targets, thereby suggesting that the new indole 7j may inhibit Mtb via a unique mechanism.

Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation

“…SAR considerations deduced from our previous works only underscored the indispensability of the 2,5-dimethylpyrrole scaffold of 1 to antimycobacterial activity and suggested the benefit of having bulky, aliphatic and lipophilic substituents on the methyleneamine side chain on C3 of the pyrrole [18][19][20][21]. On that account, next we sought to expand the scope of the investigation focusing on the N1 position and C3 of the pyrrole nucleus as key sites for diversification (Fig.…”

“…Furthermore, the N-phenyl moiety was replaced with other rings including pyridine to incorporate heteroaromaticity, as well as with more flexible benzyl or picolyl moieties to interrogate whether free rotation at that position has any effect. The synthesis of this series of pyrrole derivatives 5a-r was achieved through an adaptation of classical synthetic methods as previously reported (Scheme 1 and Table 1) [20,21]. Scheme 1.…”

“…The investigations were pivotal in identifying the 2,5-dimethylpyrrole scaffold as one of the key features requisite for antimycobacterial activity, wherein further optimization led to the identification of 1 with enhanced potency against M. tuberculosis and intracellular mycobacteria (Fig. 1) [18][19][20][21]. Altogether, these findings have provided the impetus for further investigation of 1.…”

Development of Hyphenated Techniques and Network Identification Approaches for Biotransformational Evaluation of Promising Antitubercular N-pyrrolyl hydrazide-hydrazone in Isolated Rat Hepatocytes

“…Varieties chemical moieties have been introduced in the urgent discovery of novel anti-tubercular agents, including hydrazones [ 9 ] and derivatives of pyrrole [ 10 , 11 ]. In addition, pyrrole-based compounds are identified as potential chemotherapeutics applicable for the inhibition of M. tuberculosis and other atypical mycobacteria, including M. avium complex, which greatly contributes to the deaths of AIDS patients [ 10 , 12 ].…”