Natural Product-Based Phenols as Novel Probes for Mycobacterial and Fungal Carbonic Anhydrases

Abstract

In order to discover novel probes that may help in the investigation and control of infectious diseases through a new mechanism of action, we have evaluated a library of phenol-based natural products (NPs) for enzyme inhibition against four recently characterized pathogen β-family carbonic anhydrases (CAs). These include CAs from Mycobacterium tuberculosis, Candida albicans, and Cryptococcus neoformans as well as α-family human CA I and CA II for comparison. Many of the NPs selectively inhibited the mycobacterial and fungal β-CAs, with the two best performing compounds displaying submicromolar inhibition with a preference for fungal over human CA inhibition of more than 2 orders of magnitude. These compounds provide the first example of non-sulfonamide inhibitors that display β over α CA enzyme selectivity. Structural characterization of the library compounds in complex with human CA II revealed a novel binding mode whereby a methyl ester interacts via a water molecule with the active site zinc.

Phenols and Polyphenols as Carbonic Anhydrase Inhibitors

“…The flavone luteolin (61), the two flavonols kaempferol (65) and isorhamnetin (68), as well as the flavonol glycosides quercetin-3-O-glucoside (77), quercetin-3-O-rhamnoside (87) and kaempferol-3-O-glucoside (88) are ubipresent flavonoids in most vegetables and fruits daily consumed, while galangin (80) is present in honey and propolis [73,74]. Among the flavonoids considered were the flavanones naringenin (81), eriodictyol (82) and hesperitin (83), which are abundant in edible Citrus spp. (e.g.…”

“…The first evidence that phenols can inhibit pathogenic CAs came from the screening of a natural product library [83] against β-CAs from M. tuberculosis, C. albicans, and C. neoformans. Screening of libraries of plant extracts and isolated constituents, although time consuming, is a valuable tool in the exploration of new scaffolds in order to discover new chemotypes to combat diseases.…”

“…Screening of libraries of plant extracts and isolated constituents, although time consuming, is a valuable tool in the exploration of new scaffolds in order to discover new chemotypes to combat diseases. The Queensland Compound Library reported by Davis et al, [83] comprised a wide range of natural and synthetic products incorporating the phenol group. Overall 21 constituents 104-124 were selected and tested (Figures 21 and 22) including eight fungal (compounds 104-109a, 112, 113 promote distinct structural and developmental procedures which influence the survival, virulence and pathogenesis of these fungi [82].…”

7-Aryl-triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrase IX and XII

“…Since many CA isoforms are involved in diverse physio/pathological conditions such as glaucoma (hCA I, II, IV and XII), edema (hCA II, IV, XIV as the most important), central nervous system (CNS)-related pathologies (hCAVII and XIV are particularly involved in the epilepsy) and tumors (hCA IX and hCA XII are strictly associated with hypoxic tumors), it is not surprising that CAIs are used in the clinic for some applications for almost 70 years [18][19][20][21][22][23][24] . Many synthetic efforts have been made for the development of specific CAIs: in the last 15 years, in addition to the classical ''tail approach'' [10][11][12][13][14][15][16][17][25][26][27][28] which is mainly applied to classical sulfonamide inhibitors and their isosters, novel CAIs scaffolds have been also identified such as the polyamines 29 , phenols [30][31][32] , dithiocarbamates [33][34][35][36] , xanthates 37 , coumarins, thiocoumarins, 2-thioxocoumarins, coumarine oximes 4,38,39 . Sulfocoumarins are the latest CAI class identified and similarly to the coumarins showed the most selective inhibition profiles against the pathologically valuable CA isoforms 1,9,[40][41][42][43][44] .…”

Benzylidene 2-Aminoimidazolones Derivatives: Synthesis and <i>in Vitro</i> Evaluation of Anti-tumor Carcinoma Activity

“…6,9,10) Many recent reports and reviews have also highlighted that Polyandrocarpamines A exhibit potent antitumor activity. 6,11,12) Phorbatopsins A which was isolated from the Mediterranean marine sponge Phorbas topsent exhibited antioxidant activity.…”