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Microbial co-cultivation is employed for awakening silent biosynthetic gene clusters (BGCs) to enhance chemical diversity. However, the selection of appropriate partners for co-cultivation remains a challenge. Furthermore, competitive interactions involving the suppression of BGCs or upregulation of known, functional metabolite(s) during co-cultivation efforts is also common. Herein, we performed an alternative approach for targeted selection of the best co-cultivation pair. Eight marine sediment-derived fungi were classified as strong or weak, based on their anti-phytopathogenic potency. The fungi were co-cultured systematically and analyzed for their chemical profiles and anti-phytopathogenic activity. Based on enhanced bioactivity and a significantly different metabolite profile including the appearance of a co-culture specific cluster, the co-culture of <i>Plenodomus influorescens</i> (strong) and <i>Pyrenochaeta nobilis</i> (weak) was prioritized for chemical investigation. Large-scale co-cultivation resulted in isolation of five polyketide type compounds: two 12-membered macrolides, dendrodolide E (<b>1</b>) and its new analog dendrodolide N (<b>2</b>), as well as two rare azaphilones spiciferinone (<b>3</b>) and its new analog 8a-hydroxy-spiciferinone (<b>4</b>). A well-known <i>bis</i>-naphtho-&#947;-pyrone type mycotoxin, cephalochromin (<b>5</b>), whose production was specifically enhanced in the co-culture, was also isolated. Chemical structures of compounds <b>1</b>&#8722;<b>5</b> were elucidated by NMR, HRMS and [&#945;]<inline-formula> <math display="inline"> <semantics> <mrow> <msubsup> <mrow></mrow> <mi mathvariant="normal">D</mi> <mn>20</mn> </msubsup> </mrow> </semantics> </math> </inline-formula> analyses. Compound <b>5</b> showed the strongest anti-phytopathogenic activity against <i>Xanthomonas campestris</i> and <i>Phytophthora infestans</i> with IC₅₀ values of 0.9 and 1.7 &#181;g/mL, respectively.