Hymenialdisine an alkaloid of oroidin class has drawn the attention of researchers owing to its unique structural features and interesting biological properties. Hymenialdisine exhibited promising ...inhibitory activity against a number of therapeutically important kinases viz., CDKs, GSK-3β etc., and showed anti-cancer, anti-inflammatory, anti-HIV, neuroprotective, anti-fouling, anti-plasmodium properties. Hymenialdisine and other structurally related oroidin alkaloids such as dibromo-hymenialdisine, stevensine, hymenin, axinohydantoin, spongicidines A-D, latonduines and callyspongisines contain pyrrolo2,3-c azepin-8-one core in common. Keeping in view of the interesting structural and therapeutic features of HMD, several structural modifications were carried around the fused-azepinone core which resulted in a number of diverse structural motifs like indolo-azepinones, paullones, aza-paullones, darpones and 5,7-dihydro-6H-benzobpyrimido4,5-d azepin-6-one. In this review, an attempt is made to collate and review the structures of diverse hymenialdisine and related fused-azepinones of synthetic/natural origin and their biological properties.
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•Discussion on hymenialdesine and related oriodin alkaloids.•An overview of the synthetic derivatives of hymenialdesine i.e. paullones, azakenpaullones and indolic derivatives of HMD.•Therapeutic properties of fused-azepinones.•SAR of synthetic derivatives of fused-azepinones.
We present a synthesis of the pentacyclic A–E ring system of palau′amine, a member of the dimeric pyrrole‐imidazole alkaloid (PIA) family. The synthesis features tandem elimination–Michael addition ...reaction to obtain cis‐fused bicyclo3,3,0octane, followed by stereoselective ketone reduction, and further elaboration to obtain the tetracyclic precursor for the Overman rearrangement reaction. The enamide‐type Overman rearrangement reaction generated the N,N′‐aminal quaternary asymmetric center at C10, and ring closure provided the desired pentacycle.
The enamide‐type Overman rearrangement reaction was effectively applied to the construction of an N,N′‐aminal quaternary center at C10 in the pentacyclic A–E ring for palau′amine.
In his most celebrated tale "The Picture of Dorian Gray", Oscar Wilde stated that "those who go beneath the surface do so at their peril". This sentence could be a prophetical warning for the ...practitioner who voluntarily challenges himself with trying to synthesize marine sponge-deriving pyrrole-imidazole alkaloids. This now nearly triple-digit membered community has been growing exponentially in the last 20 years, both in terms of new representatives and topological complexity--from simple, achiral oroidin to the breathtaking 12-ring stylissadines A and B, each possessing 16 stereocenters. While the biosynthesis and the role in the sponge economy of most of these alkaloids still lies in the realm of speculations, significant biological activities for some of them have clearly emerged. This review will account for the progress in achieving the total synthesis of the more biologically enticing members of this class of natural products.
We have prepared three alkaloids from the Agelas sponges, clathrodin, hymenidin and oroidin, and a series of their synthetic analogues, and evaluated their inhibitory effect against six isoforms of ...the Kv1 subfamily of voltage-gated potassium channels, Kv1.1-Kv1.6, expressed in Chinese Hamster ovary (CHO) cells using automated patch clamp electrophysiology assay. The most potent inhibitor was the (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dichloro-1H-pyrrole-2-carboxamide (6g) with IC50 values between 1.4 and 6.1 μM against Kv1.3, Kv1.4, Kv1.5 and Kv1.6 channels. All compounds tested displayed selectivity against Kv1.1 and Kv1.2 channels. For confirmation of their activity and selectivity, compounds were additionally evaluated in the second independent system against Kv1.1-Kv1.6 and Kv10.1 channels expressed in Xenopus laevis oocytes under voltage clamp conditions where IC50 values against Kv1.3-Kv1.6 channels for the most active analogues (e.g. 6g) were lower than 1 μM. Because of the observed low sub-micromolar IC50 values and fairly low molecular weights, the prepared compounds represent good starting points for further optimisation towards more potent and selective voltage-gated potassium channel inhibitors.
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•Alkaloids hymenidin and oroidin inhibited Kv1.3-Kv1.6 channels with IC50 values in the low μM range.•Two expression systems were used to express Kv1 channels, CHO cells and Xenopus laevis oocytes.•The best analog displayed IC50 of 1.4 μM, 1.5 μM, and 1.6 μM against Kv1.3, Kv1.4, and Kv1.6 channels.
A convenient strategy for the scalable synthesis of the 2-aminoimidazole alkaloids, clathrodin, oroidin, and hymenidin derived from marine Agelas species and their analogs possessing a saturated or ...unsaturated linker moiety is described. The key intermediates, 4-(3-aminopropyl)-1H-imidazol-2-amine and (E)-4-(3-aminoprop-1-en-1-yl)-1H-imidazol-2-amine were obtained through two different synthetic pathways starting from l-ornithine and benzyl 1,2-dihydropyridine-1-carboxylate respectively, using (i) an innovative combination of Weinreb amide strategy with di-Boc protection, and (ii) a modified pyridine-1(2H)-carboxylate based strategy. Convenient access to these 2-aminoimidazole amines is crucial for the synthesis of libraries of clathrodin, oroidin, and hymenidin analogs.
Oroidin (1), (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dibromo-1H-pyrrole-2-carboxamide, is a pyrrole alkaloid isolated from the marine sponge Agelas oroides. Routine screening in a panel of ...twelve cancer cell lines revealed 1 to be poorly cytotoxic with the 50% growth inhibition concentration (GI50) of 42μM in MCF-7 (breast) cells and 24μM in A2780 (ovarian) cells and >50μM in all other cell lines tested. The development of eight focused libraries comprising thirty compounds total identified N-(biphenyl-4-ylmethyl)-1H-pyrrole-2-carboxamide (4l), N-benzyl-4,5-dibromo-1H-pyrrole-2-carboxamide (5a) and N-(biphenyl-4-ylmethyl)-4,5-dibromo-1H-pyrrole-2-carboxamide (5l) as potent inhibitors of cell growth in our panel of cell lines. Of these compounds GI50 values of <5μM were observed with 4l against HT29 (colon) and SW480 (colon); 5a against HT29; and 5l against HT29, SW480, MCF-7, A431 (skin), Du145 (prostate), BE2-C (neuroblastoma) and MIA (pancreas) cell lines. As a cancer class, colon cancer appears to be more sensitive to the oroidin series of compounds, with analogue 5l being the most active.
Pyrrole-2-aminoimidazole compounds are found in marine organisms, mainly as secondary metabolites in various marine sponges. Studies of natural pyrrole-2-aminoimidazole compounds showed that they ...possess different pharmacological properties, such as antimicrobial, antibiofilm, immunosuppressive and anticancer activities. Many analogs of the natural compounds have been synthesized to improve their biological activities. This review focuses on the antibacterial and antibiofilm potentials of natural pyrrole-2-aminoimidazoles and their synthetic analogs and derivatives, as well as on the structure-activity relationships of the most promising compounds. Known molecular targets of these compounds in bacterial cells are also described here, as is the synergistic activity of the pyrrole- 2-aminoimidazoles and conventional antibiotics.
We had earlier used Oroidin, a 2‐aminoimidazole‐pyrrole natural microbial biofilm inhibitor, as a structural prototype to develop its 4/5‐acyl modified form as an anti‐biofilm lead for further ...optimization. Herein, as a part of our efforts towards that direction, we report the design, synthesis, as well as anti‐bacterial, anti‐biofilm, and fungal adhesion inhibition activities of various 4/5‐aroyl‐2‐aminoimidazoles. These simplified Oroidin analogues are moderately active against bacterial biofilms and attest to the need for an aliphatic acyl linker that was part of the original 4/5‐acyl modified Oroidin lead. From our studies, protonation propensity of the 2‐aminoimidazole group of the series emerges as an important pre‐requisite for potent antibiofilm activity. Also, the fungal biofilm screening studies identified analogue 8 b as an active molecule.
A series of 4/5‐aroyl‐2‐aminoimidazoles were synthesized and evaluated for their efficiency in inhibiting the bacterial biofilm formation. The in‐vitro activity results and cheminformatic analysis revealed importance of 2‐aminoimidazole's pKa and its protonation propensity as the key factors for the activity. The library was also tested for fungal cell adhesion inhibition and revealed that appending dibromomaleimide is beneficial for the activity.
Herein, we describe indole-based analogues of oroidin as a novel class of 2-aminoimidazole-based inhibitors of methicillin-resistant Staphylococcus aureus biofilm formation and, to the best of our ...knowledge, the first reported 2-aminoimidazole-based inhibitors of Streptococcus mutans biofilm formation. This study highlighted the indole moiety as a dibromopyrrole mimetic for obtaining inhibitors of S. aureus and S. mutans biofilm formation. The most potent compound in the series, 5-(trifluoromethoxy)indole-based analogue 4b (MBIC50=20μM), emerged as a promising hit for further optimisation of novel inhibitors of S. aureus and S. mutans biofilms.
Marine organisms produce secondary metabolites that may be valuable for the development of novel drug leads as such and can also provide structural scaffolds for the design and synthesis of novel ...bioactive compounds. The marine alkaloids, clathrodin and oroidin, which were originally isolated from sponges of the genus, Agelas, were prepared and evaluated for their antimicrobial activity against three bacterial strains (Enterococcus faecalis, Staphylococcus aureus and Escherichia coli) and one fungal strain (Candida albicans), and oroidin was found to possess promising Gram-positive antibacterial activity. Using oroidin as a scaffold, 34 new analogues were designed, prepared and screened for their antimicrobial properties. Of these compounds, 12 exhibited >80% inhibition of the growth of at least one microorganism at a concentration of 50 µM. The most active derivative was found to be 4-phenyl-2-aminoimidazole 6h, which exhibited MIC₉₀ (minimum inhibitory concentration) values of 12.5 µM against the Gram-positive bacteria and 50 µM against E. coli. The selectivity index between S. aureus and mammalian cells, which is important to consider in the evaluation of a compound's potential as an antimicrobial lead, was found to be 2.9 for compound 6h.
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