Naturally occurring Diels-Alder-type adducts from Morus nigra as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B

Pharmacological Properties of Morus nigra L. (Black Mulberry) as A Promising Nutraceutical Resource

“…In this respect, demand for new medications with novel therapeutic targets such as protein tyrosinase phosphatases (PTPs) is growing [30,31]. Mascarello et al [32] evaluated the anti-tuberculosis activity of Diel–Alder-type adducts from M. nigra root bark to determine their potential as candidates for M. tuberculosis PTP inhibitor. A total of eight compounds (Kuwanon L, G, and H; cudraflavanone A; morusin, oxyresveratrol; chalcomoracin; and norartocarpetin) were isolated from M. nigra .…”

A unique high-diversity natural product collection as a reservoir of new therapeutic leads

“…122 In 2018, additional D-A-type adducts and other natural products isolated from M. nigra roots bark were screened. 85 The two most potent compounds that were found to inhibit PtpB at sub-micromolar concentrations were again two D-A-type adducts, namely kuwanon G (68) and kuwanon H (69). These results highlighted the relevance of the D-A-type scaffold in the development of promising candidates for the treatment of tuberculosis.…”

“…A subsequent plant-based computational screening highlighted kuwanon G (68) and kuwanon H (69) as PtpB inhibitors with sub-micromolar potency and efficacy against Mtb survival in vitro (see section 4.2 and Chart 1). [83][84][85] Structure-based approaches have played a crucial role in the study of the Hedgehog (Hh) signalling pathway, both in terms of understanding the structural features of Gli1 binding to DNA, and with regard to identifying and optimizing small molecule inhibitors that act either at upstream levels, i.e. targeting the smoothened receptor (SMO), or at downstream levels, i.e.…”

“…These results highlighted the relevance of the D-A-type scaffold in the development of promising candidates for the treatment of tuberculosis. 85 Another structurally very similar D-A-type adduct, namely kuwanon L (70), was also extracted and isolated from the root bark of M. nigra L. This compound was evaluated for anti-HIV activity and was shown to be an allosteric inhibitor of HIV-1 integrase in vitro.…”

Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections

“…45,46 Several studies have shown the possibility of selectively inhibiting M. tuberculosis PtpB over human phosphatases, which can result from structural differences such as PtpB containing alphahelices that can occlude the active site, yet are mobile enough to allow substrate and competitive inhibitors to bind. 45,[47][48][49][50][51][52][53][54] Furthermore, previous studies have demonstrated the feasibility of inhibiting M. tuberculosis PtpB with small molecules and reducing bacterial loads in macrophages. 45,47,48 In their 2007 study, Grundner et al reported a crystal structure of PtpB in complex with the selective inhibitor (oxalylamino-methylene)-thiophene sulfonamide (OMTS - Figure 2A).…”