## 6 Biological Activity of the Hapalindole-Type Alkaloids
### Antimicrobial Activity  
Arguably, the primary bioactivity of the haplindole-type has been inhibition of microbes including bacteria, fungi and algae. In fact, the haplindoles, as the archetypal member of the class, were first isolated from _H. fontanalis_ based on antimicrobial--and specifically antialgal--activity of extracts [29; 30]. Subsequent studies, in the course of identifying new variants, have confirmed antimicrobial activity of both tri- and tetracyclic haplindoles [34; 42; 69]. Most recently, [PERSON] _et al._[34] reported the isolation of several haplindoles including a novel variant, haplindole X, and demonstrated relatively potent activity (MIC \(\geqslant\) 2.5 uM) of this congener against _Mycobacterium tuberculosis_, and the yeast, _Candida albicans_, as well as potent activity of several other haplindoles (_i.e._, A, I, J) and presumptive oxidative products (_i.e._, haplonamide H). It is noteworthy that both chlorinated and non-chlorinated congeners (e.g., haplindole A and J) display similar antimicrobial activity [34]. Furthermore, comparable antimicrobial activity has been reported for 12-_epi_-hapalindoles [62; 64]. Relatively limited information exists, on the other hand, as to the role of the variable C-11 functional group of the haplindoles; in particular, studies have generally focused on the more common isonitrile-bearing variants compared, for example, to the less common isothiocyanate congeners. [PERSON] _et al._[29], in the original isolation of the haplindoles, did indicate that haplindole A \"was responsible for most of the antialgal and antimycotic activity of _H. fontinals_,\" and reported no biological activity for haplindole B, the isothianate equivalent, isolated as a minor component in the same study; however, no specific bioactivity data were, in fact, presented in this study. That said, the thiocarbamate-containing variant, haplindole  
T, was found to be antibacterial against a range of Gram-positive and -negative representatives, and quantitatively comparable to other hapalindoles in this regard [31]. In addition to inhibition of heterotrophic bacteria and fungi, it has been shown that hapalindoles effectively inhibit the growth of other algae, and cyanobacteria, in particular. [PERSON] _et al._[63] specifically used antialgal activity to guide isolation of several metabolites from an Amazonian isolate of _Fischerella_, and identified two putative hapalindoles, including the 12-_epi_-hapalindole F (as confirmed by NMR studies), which inhibited a representative strain of the cyanobacterial genus, _Synechococcus_. This finding is notable in that hapalindole F is an isothiocyanate-bearing variant; however, [PERSON] _et al._[62] also demonstrated inhibition of cyanobacteria and eukaryotic green algae by the isonitrile counterpart of 12-_epi_-hapalindole F (_i.e._, 12-_epi_-hapalindole E). Similar to the hapalindoles, [PERSON] _et al._[36] originally isolated ambiguities based on inhibition of several representative fungi including _Aspergillus oryzae_, _Candida albicans_, _Penicillium notatum_, _Saccharomyces cerevisiae_ and _Trichophyton metagroophytes_. And subsequent studies [37; 38; 42] have, likewise, demonstrated diverse antibacterial and antifungal activity of both tetra- and pentacyclic ambiguities encompassing rather diverse structural variability within the sub-class (_i.e._, ambiguities A-P). Also similar to the hapalindoles, both chlorinated and non-chlorinated (at C-13) variants generally showed comparable antimicrobial activity; however, unlike hapalindoles, there have to-date not been any isothianate variants of the ambigiunes reported. That said a multiple nitrile-containing ambiguities have been identified. In particular, ambiguine G nitrile was isolated from _F. ambiguu_, and shown to have antibacterial and antifungal activity comparable to ambiguine isonitriles. More recently, the fischambiguines were isolated, alongside several previously recognized ambiguities, from _F.