The emergence and spread of drug-recalcitrant Plasmodium falciparum parasites threaten to reverse the gains made in the fight against malaria. Urgent measures need to be taken to curb this impending challenge. The higher plant-derived sesquiterpene, quinoline alkaloids, and naphthoquinone natural product classes of compounds have previously served as phenomenal chemical scaffolds from which integral antimalarial drugs were developed. Historical successes serve as an inspiration for the continued investigation of plant-derived natural products compounds in search of novel molecular templates from which new antimalarial drugs could be developed. The aim of this study was to identify potential chemical scaffolds for malaria drug discovery following analysis of historical data on phytochemicals screened in vitro against P. falciparum. To identify these novel scaffolds, we queried an in-house manually curated database of plant-derived natural product compounds and their in vitro biological data. Natural products were assigned to different structural classes using NPClassifier. To identify the most promising chemical scaffolds, we then correlated natural compound class with bioactivity and other data, namely (i) potency, (ii) resistance index, (iii) selectivity index and (iv) physicochemical properties. We used an unbiased scoring system to rank the different natural product classes based on the assessment of their bioactivity data. From this analysis we identified the top-ranked natural product pathway as the alkaloids. The top three ranked super classes identified were (i) pseudoalkaloids, (ii) naphthalenes and (iii) tyrosine alkaloids and the top five ranked classes (i) quassinoids (of super class triterpenoids), (ii) steroidal alkaloids (of super class pseudoalkaloids) (iii) cycloeudesmane sesquiterpenoids (of super class triterpenoids) (iv) isoquinoline alkaloids (of super class tyrosine alkaloids) and (v) naphthoquinones (of super class naphthalenes). Launched chemical space of these identified classes of compounds was, by and large, distinct from that of ‘legacy’ antimalarial drugs. Our study was able to identify chemical scaffolds with acceptable biological properties that are structurally different from current and previously used antimalarial drugs. These molecules have the potential to be developed into new antimalarial drugs.

耐药性恶性疟原虫的出现和传播可能会逆转抗击疟疾所取得的成果。需要采取紧急措施来遏制这一迫在眉睫的挑战。高等植物来源的倍半萜、喹啉生物碱和萘醌天然产物类化合物以前曾作为显着的化学支架，用于开发完整的抗疟药物。历史上的成功为继续研究植物源性天然产物化合物提供了灵感，以寻找可开发新抗疟药物的新型分子模板。本研究的目的是在分析体外筛选的针对恶性疟原虫的植物化学物质的历史数据后，确定用于发现疟疾药物的潜在化学支架。为了识别这些新颖的支架，我们查询了内部手动管理的植物源性天然产物化合物及其体外生物学数据的数据库。使用 NPClassifier 将天然产物分配到不同的结构类别。为了确定最有前途的化学支架，我们将天然化合物类别与生物活性和其他数据相关联，即（i）效力，（ii）抗性指数，（iii）选择性指数和（iv）理化性质。我们使用公正的评分系统根据生物活性数据的评估对不同的天然产品类别进行排名。从这一分析中，我们确定了排名第一的天然产物途径是生物碱。排名前三的超类是 (i) 拟生物碱、(ii) 萘和 (iii) 酪氨酸生物碱，排名前五的类是 (i) 苦木素（超类三萜类）、(ii) 甾体生物碱（超类拟生物碱） ) (iii) 环桉倍半萜类化合物（超类三萜类化合物） (iv) 异喹啉生物碱（超类酪氨酸生物碱类）和 (v) 萘醌类（超类萘类）。这些已确定的化合物类别的已推出的化学空间总体上与“传统”抗疟药物不同。我们的研究能够识别出具有可接受的生物学特性的化学支架，这些支架在结构上与当前和以前使用的抗疟药物不同。这些分子有潜力被开发成新的抗疟药物。