Inhibition of Hill Reaction by 2-Azido-s-triazine Derivatives: QSAR Study with Molecular Connectivity Indices Milan Šoškić Department of Chemistry, Faculty of Agricultural Sciences, University of Zagreb. 41000 Zagreb. Croatia, Yugoslavia Aleksandar Sabljić Institute Ruder Boskovic, P.O.B. 1016. 41001 Zagreb. Croatia. Yugoslavia Z. Naturforsch. 44c, 255—261 (1989); received November 29, 1988 2-Azido-s-Triazines, Connectivity Indices. Inhibition of Hill Reaction. Photosystem II, OSAR Modelling This study was undertaken to find a simple and accurate structural parameters for the quantita tive description of inhibitory potency of 2-azido-s-triazines in Hill reaction and to gain more information about the mechanism of inhibition on molecular level. A very good correlation (r = 0.946) was obtained between the plS(>values (the negative logarithm of the molar concentra tion that causes 50% inhibition) and the valence zero-order and the difference between the second-order and the valence second-order molecular connectivity indices. This model, when compared with the empirical models based on the 1-octano/water partition coefficients and the chromatographic retention data, shows superior performance in accuracy and range of applicabili ty. In addition, the direct correspondence between molecular structure and above connectivity indices makes it possible to locate structural features responsible for the inhibitory potency of 2-azido-s-triazines in Hill reaction. From our OSAR analysis, the interaction between the chloro plast receptor site and 2-azido-s-triazines, which causes inhibition of Hill reaction, is primarily influenced by the size of alkylamino substituents and it accounts for the most variation in the plS(> data. The structural features of secondary importance that control the magnitude of pUo's are the polarity of alkylamino chains and the degree of branching on alpha carbon atom of R: alkylamino substituent. Compared with the main factor, the size of alkylamino substituents, they can be viewed as a fine tuning elements for the inhibitory potency of 2-azido-s-triazines. Introduction The majority of commercial herbicides act as in hibitors of photosynthesis in chloroplast. Numerous biochemical and biophysical experiments, mainly on isolated chloroplast, indicated [1—5] that those struc turally different classes of herbicides (phenylureas, s- triazines, as-triazinones, uracils, pyridazinones, ben- zimidazoles, phenols, etc.) all bind competitively to a protein with a molecular weight of 32,000—34,000 within the thylakoid membrane and inhibit the elec tron flow on the reducing side of photosystem II [6 ]. Photosystem II inhibitors can be differentiated by their mode of action into two chemically different classes that are referred to as the diuron/triazine type and the phenol type. The in vitro inhibitory potency of those herbicides is determined from their ability to inhibit the Hill reaction [7], In our recent article [8 ], a very successful QSAR (Quantitative Structure Ac- Reprint requests to Dr. A. Sabljic. Verlag der Zeitschrift für Naturforschung. D-7400 Tübingen 0341 - 0382/89/0300- 0255 SOI. 30/0 tivity Relationship) model [9], based on the molecu lar connectivity indices, was formulated for the in hibition of the Hill reaction by 3-alcoxyuracils (the diuron/triazine type inhibitors). In this study we will extend our investigation on s- triazines and their ability to inhibit the Hill reaction. We will try to create the QSAR model for 2-azido-s- triazines with various alkylamino substituents on positions 4 and 6 (see structure 1). 1 This class of s-triazines is selected for our study because of its structural homogeneity. The molecular connectivity indices [10—13] will be used as the quan titative descriptors for the molecular structure of 2 - azido-s-triazines. They have been demonstrated to be very successful in creating numerous QSAR mod els with physico-chemical properties [10—14], bio-