Strigolactone analogues and mimics derived from phthalimide, saccharine, p-tolylmalondialdehyde, benzoic and salicylic acid as scaffolds Binne Zwanenburg ⇑ , Alinanuswe S. Mwakaboko 1 Radboud University Nijmegen, Institute for Molecules and Materials, Department of Organic Chemistry, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands article info Article history: Received 11 July 2011 Revised 17 October 2011 Accepted 18 October 2011 Available online 24 October 2011 Keywords: Strigolactone Parasitic weeds Bioassay Striga Orobanche Germination Molecular mechanism Alternative mode of action New type stimulants abstract A series of new strigolactone (SL) analogues is derived from simple and cheap starting materials. These SL analogues are designed using a working model. The first analogue is a modified Nijmegen-1, the second contains saccharin as substituent (bio-isosteric replacement of a carbonyl in Nijmegen-1 by a sulfonyl group) and the third one is derived from p-tolylmalondialdehyde. These new SL analogues are apprecia- bly to highly active as germination stimulants of seeds of Striga hermonthica and Orobanche cernua. The SL analogue derived from saccharin is the most active one. A serendipitous and most rewarding finding is that the compound obtained by a direct coupling of sac- charin with the chlorobutenolide exhibits a high germination activity especially towards O. cernua seeds. Two other SL mimics are obtained from benzoic and salicylic aid by a direct coupling reaction with chlo- robutenolide, both of them are very active germinating agents. These SL mimics represent a new type of germination stimulants. A tentative molecular mechanism for the mode of action of these SL mimics has been proposed. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Strigolactones (SLs) are currently in the focus of interest as they are considered as a new type of plant hormones. 1–6 Natural strigo- lactones have been isolated from root exudates of various plants, especially those that are parasitised by the noxious weeds Striga and Orobanche spp. The first natural SL that has been isolated is strigol (1) 7 (Fig. 1). Full details of the structure of this germination stimulant for seeds of the just mentioned weeds were described about 20 years after its initial isolation. 8 Up to now several natural germination stimulants have been isolated and identified from the root exudates of both host and nonhost plants. 7,9–14 The structures of SLs invariably contain four rings, the main structural differences are encountered in the AB part, whereas all stimulants contain the same D-ring. 12–15 It is highly relevant to mention that these stimu- lants occur only in minute amounts in root exudates. The production of strigol per plant is estimated to be ca. 25–30 pg per day. 16,17 As a consequence the isolation and identification of natural SLs is extre- mely difficult. The natural life cycle of the parasitic weeds Striga and Orobanche spp. involves the germination of their seeds induced by a SL exuded by the roots of the host plant. This is followed by the formation of a radicle from the seed and its subsequent attachment to the host roots allowing the developing parasite to take nutrients, hormones and water from the host plant which, as a consequence, will suffer and not be able to grow normally. 18 Infestation of cereal crops (main staple food) by Striga results in considerable crop losses, which is considered to be the major obstacle to food production in Central and Southern Africa. 19 The estimated loss of cereal crop amounts to of million of tons each year. 19,20 Weed pest control is therefore of utmost importance. 19,20 The concept of suicidal germi- nation is an appealing approach to control these noxious weeds. 15,21–25 In this approach the soil is treated with stimulant in absence of a host, hence the germinated seeds cannot develop and will die. The natural stimulants cannot be used for this purpose as their synthesis 26 is far too laborious and expensive. Therefore, ana- logues have been prepared in which the bioactivity is predominantly retained. The first successful series of analogues are the GR com- pounds, 27 as is exemplified by GR 24 (3) 28 (Fig. 1). An extensive study of structure–activity relationship revealed that the bioactiphore resides in the CD part of the molecule. 29,30 In addition, a molecular mechanism has been proposed for the initial reaction of the stimulants with protein receptor in the seeds (Scheme 1). 29,30 In essence this is nucleophilic addition to the a, b-unsaturated unit followed by a retro reaction with the concurrent elimination of the D-ring. Combining the information of the bioacti- phore and the molecular mechanism leads to a working model for designing new germination stimulants as shown in Figure 2. 15 0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2011.10.057 ⇑ Corresponding author. Tel.: +31 24 3653159. E-mail address: B.Zwanenburg@science.ru.nl (B. Zwanenburg). 1 Current address: Department of Chemistry, University of Dar es Salaam, PO Box 35061, Dar es Salaam, Tanzania. Bioorganic & Medicinal Chemistry 19 (2011) 7394–7400 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc