QSAR Studies on a Series of 7,8‐Dialkyl‐1,3‐diaminopyrrolo‐[3,2‐f]quinazolines with Anticancer Activity

Abstract

The quantitative structure-activity relationship (QSAR) studies on a series of 7,8-dialkyl-1,3-diaminopyrrolo-[3,2-f]quinazolines, dihydrofolate reductase (DHFR) inhibitors as potential anticancer agents, have been carried out by using the density functional theory (DFT) method, molecular mechanics method (MM＋) and statistical method. Some QSAR models based on their lipophilic and steric parameters were built up via a stepwise regression analysis. It is very interesting to find that the established optimal QSAR equation involves only two descriptors: lipophilicity indexes Clog P and Clog P 2 . However, such descriptors can quite well describe a significant statistic quality and have a remarkable predictive activity according to the square of adjusted correlation coefficient ( 2 A R ＝0.937) and the square of cross-validation coefficient (q 2 ＝0.911) of this equation. The results show that the lipophilicity is a main factor affecting the anticancer activity of this series of antimetastatic agents, and the obtained equation describes a parabolic correlation between pIC 50 and Clog P, and indicates a suitable range of Clog P (around 4.43) being very important for optimal pIC 50 values. These QSAR studies can offer some useful references for understanding the action mechanism and performing the molecular design or modification of this series of antimetastatic agents.

A Combined 2D‐ and 3D‐QSAR Study on Analogues of ARC‐111 with Antitumor Activity

“…From Table 2, we can find that compound 9 with an optimal Clog P value (3.145) has the most activity among this dataset, whereas other compounds with larger or lower Clog P value all have lower activities. The trend in hydrophobicity effects of these compounds is in agreement with that of some other series of compounds with antitumor activities [41].…”

Cluster Analysis and QSAR Study of Some Anti‐hepatitis B Virus Agents Comprising 4‐Aryl‐6‐chloro‐quinolin‐2‐ones and 5‐Aryl‐7‐chloro‐1,4‐benzodiazepines

“…38 From the cross-validation tests, 2 CV r of 0.874 indicated that the results obtained for the best QSAR equations were not by chance correlation. 28 The derived 2D-QSAR model (1) thus was robust and found satisfactory for predicting the activities of the test set (Table 1).…”

The chemistry and pharmacology of privileged pyrroloquinazolines

“…19, 20 These structure-activity relationship (SAR) studies showed that a large hydrophobic group appended to N 7 was optimal for DHFR inhibition. 19, 32 Therefore, the majority of structural analogs of 2 in the literature possess an N 7 -alkyl group. 19, 20 …”

“…24 Both of the compounds significantly blocked the binding between PAR1 on the platelet membranes and a PAR1 peptidic agonist ha-TRAP [Ala-Phe(p-F)-Arg-Cha-HArg-Tyr-NH 2 ] 45 with IC 50 values of 56 and 52 nM, respectively. Although none of these PAR antagonists were evaluated for DHFR inhibition, 47 would be predicted to be a sub-nM to low nM DHFR inhibitor based on known SAR, 19, 32, 35 suggesting its preferential selectivity towards DHFR. However, it is well-accepted that primary amino groups at N 1 and N 3 are required for optimal DHFR inhibition.…”