ABSTRACT
Atherosclerosis is an inflammatory disorder of the vasculature and one of the underlying causes of cardiovasculardiseases. Numerous preventative and therapeutic approaches are being explored to limit the morbidity and mortalityof this disease. Nevertheless, some of the treatments cost greatly and contributed to various side effects; for example,statin therapy is associated with substantial residual cardiovascular risk as well as issues such as tolerability and patientdependent efficacy. Currently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has been attractinginterests in the drug discovery of atherosclerosis treatment, but ezetimibe, a successful PCSK9 inhibitor, is an expensivemonoclonal antibody. Thus, exploring new PCSK9 inhibitors is crucial in overcoming this constraint. In the previouswork, aaptaminoids and methyl benzoate were isolated from marine sponges Aaptos aaptos and Acanthaster planci,respectively. These compounds enhance the transcription of the peroxisome proliferator-activated receptor gamma(PPARγ) in the luciferase assay. PPARγ agonist was hypothesized to inhibit the expression of the PCSK9 gene becausethe former is a transcription factor toward the latter. The synthesis of three aaptaminoids and 11 methyl benzoatederivative was carried out to address its potential as a PCSK9 inhibitor. The structure of the synthesized compound waselucidated using nuclear magnetic resonance spectral and electron impact mass spectral data. The PCSK9 inhibitoryactivities were determined by luciferase assay. Four aaptaminoids, such as aaptamine, N1,N4-bisbenzylaaptamine,N4-[(3,4,5-trimethoxy)benzyl]aaptamine, and N1-[(3,4,5-trimethoxy)benzyl]aaptamine, and one benzamide derivative,N-(2,3-dihydro-1H-inden-2-yl)-2-methoxybenzamide, were found to inhibit the expression of PCSK9 gene.
ABSTRACT
Aims@#Endophytic fungi are microorganisms that live asymptomatically within plant tissues, producing a wide range of metabolites, including compounds potentially useful for drug development. We investigated endophytic fungi from Maliau Basin, Sabah to identify strains producing bioactive compounds, notably with antimicrobial activity. @*Methodology and results@#A total of 23 plants were sampled yielding 345 endophytic fungal isolates. Of these, 44 isolates were screened for antimicrobial activity against nine species of bacteria and fungi, revealing 14 endophytes producing bioactive metabolites. Crude fungal extracts were obtained from broth cultures of endophytic isolates with promising activity while the fungal strains were identified using molecular methods. The crude extract of endophyte MB4 WA10, isolated from Callophyllum sp. (bintangor) showed IC50 of 2.6 mg/mL against S. aureus and 0.6 mg/mL against B. subtilis while the extract of MB22 WA16, an isolate identified as Valsaceae sp., was also active against S. aureus with an IC50 of 1.37 mg/mL. Another isolate, namely MB5 L4 (WA), was identified as a Phomopsis sp. and its extract was the most active against S. aureus with an IC50 of 1 mg/mL. The HPLC fraction of this fungal extract with the highest inhibition (92.37%) of S. aureus was purified for compound isolation and identification. A polyketide compound, 2,3-dihydro-2- hydroxy-2,4-dimethyl-5-trans-propenylfuran-3-one (C9H12O3), with molecular weight of 168.192 was identified based on mass spectral and NMR data analysis. This previously identified compound is known to have other antimicrobial properties. @*Conclusion, significance and impact of study@#Rainforests in Malaysia, especially Maliau Basin, harbour many species of fungal endophytes, producing useful bioactive compounds that may be explored for further potential uses, including antimicrobial activity.