Inhibition of biofilm formation by conformationally constrained indole-based analogues of the marine alkaloid oroidin.

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 = 20 µM), emerged as a promising hit for further optimisation of novel inhibitors of S. aureus and S. mutans biofilms.

Synthesis and anticancer activity of focused compound libraries from the natural product lead, oroidin.

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 42 µM in MCF-7 (breast) cells and 24 µM in A2780 (ovarian) cells and >50 µM 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 <5 µM 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.

Fused-azepinones: Emerging scaffolds of medicinal importance.

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-3ß 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 pyrrolo[2,3-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-benzo[b]pyrimido[4,5-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.

A submarine journey: the pyrrole-imidazole alkaloids.

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.

Antibacterial and Antibiofilm Potentials of Marine Pyrrole-2-Aminoimidazole Alkaloids and their Synthetic Analogs.

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.

Marine alkaloid oroidin analogues with antiviral potential: A novel class of synthetic compounds targeting the cellular chaperone Hsp90.

Marine organisms and their metabolites are a diverse source of scaffolds for potential pharmacological molecular probes and, less frequently, for pharmaceutical lead compounds. In this study, 157 synthetic analogues of marine sponge-derived alkaloids clathrodin and oroidin were screened against replicon models of two RNA viruses, hepatitis C (HCV) and Chikungunya virus (CHIKV) as part of a larger screening project. Four compounds were found to selectively inhibit the HCV replicon (IC50 1.6-4.6 µm). These belong to the 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole class of compounds originally designed to target the ATP-binding site of bacterial DNA gyrase. The ATP-binding site of this bacterial protein has high structural similarity to the ATP-binding site of heat-shock protein 90 (Hsp90), a host cell chaperone universally required for viral replication, which led us to examine inhibition of Hsp90 as the compounds' potential mechanism of action. Binding of the four hit compounds to Hsp90 was evaluated through microscale thermophoresis and molecular modeling, which supported our hypothesis of interaction with Hsp90 (Kd 18-79 µm) as basis for the compounds' antiviral activity. The presented novel structural class of small molecules that target the Hsp90 ATP-binding site has excellent potential for further antiviral drug development because of the compounds' low toxicity and synthetic accessibility.

Clathrodin, hymenidin and oroidin, and their synthetic analogues as inhibitors of the voltage-gated potassium channels.

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.

Evaluation of a 2-aminoimidazole variant as adjuvant treatment for dermal bacterial infections.

2-Aminoimidazole (2-AI)-based compounds have been shown to efficiently disrupt biofilm formation, disperse existing biofilms, and resensitize numerous multidrug-resistant bacteria to antibiotics. Using Pseudomonas aeruginosa and Staphylococcus aureus, we provide initial pharmacological studies regarding the application of a 2-AI as a topical adjuvant for persistent dermal infections. In vitro assays indicated that the 2-AI H10 is nonbactericidal, resensitizes bacteria to antibiotics, does not harm the integument, and promotes wound healing. Furthermore, in vivo application of H10 on swine skin caused no gross abnormalities or immune reactions. Taken together, these results indicate that H10 represents a promising lead dermal adjuvant compound.

Chemistry and Biology of the Pyrrole-Imidazole Alkaloids.

More than a decade after our last review on the chemistry of the pyrrole-imidazole alkaloids, it was time to analyze once more the developments in that field. The comprehensive article focusses on the total syntheses of pyrrole-imidazole alkaloids that have appeared since 2005. The classic monomeric pyrrole-imidazole alkaloids have all been synthesized, sometimes primarily to demonstrate the usefulness of a new method, as in the case of the related molecules agelastatin A and cyclooroidin with more than 15 syntheses altogether. The phakellin skeleton has been made more than 10 times, too, with a focus on the target structure itself. Thus, some of the pyrrole-imidazole alkaloids are now available in gram amounts, and the supply problem has been solved. The total synthesis of the dimeric pyrrole-imidazole alkaloids is still mostly in its pioneering phase with two routes to palau'amine and massadine discovered and three routes to the axinellamines and ageliferin. In addition, the review summarizes recent discoveries regarding the biological activity of the pyrrole-imidazole alkaloids. Regarding the biosynthesis of sceptrin, a pathway is proposed that starts from nagelamide I and proceeds via two electrocyclizations and reduction.