Synthesis and Antihyperlipidemic Activity of Some Novel Condensed 2-Chloroalkyl-4-chloro/hydroxy-5,6-disubstituted Pyrimidines

Abstract

Synthesis and antihyperlipidemic activity of a series of novel condensed 2-chloroalkyl-4-chloro/hydroxy-5,6-di-substituted pyrimidines are described. The design of these compounds is based on the earlier QSAR study on the antihyperlipidemic 2-substituted methylthienopyrimidin-4-ones. The newly synthesized condensed 4-chloro-2-chloroalkylpyrimidines (IIIa-n) have exhibited much superior antihyperlipidemic activity, compared to their earlier reported 4-hydroxy analogs. Notably, in this series, five compounds, IIIa, IIIb, IIIc, IIIi and IIIm showed good ability to reduce total cholesterol and two compounds, IIIa and IIIk exhibited better reduction in serum triglycerides. All the newly synthesized compounds have been evaluated by the Triton WR 1339 induced hyperlipidemia in albino Wistar rats model for antihyperlipidemic activity, and their activity is superior to that exhibited by the standard gemfibrozil used in the study. A 3D QSAR study has also been performed to delineate the effect of the substituents at 5 and 6 positions on the antihyperlipidemic activity of 2-chloromethyl-5,6-substituted thieno(2,3-d) pyrimidin-4(3H)-ones (IIa-e).

The Synergy of Combined Use of DMSO and Bronsted Acid (Ionic Liquid) as a Catalyst Part I: Efficient Niementowski Synthesis of Modified Quinazolinones

“…In continuation of our ongoing work on condensed thienopyrimidines and quinazolines [30,31], we herein report the fused heterocyclic derivatives of thienopyrimidine and quinazoline as divalent and ring equivalent isosteres of Rutaecarpine. Hence a series of novel heterocyclic compounds belonging to thienopyrimidine fused with quinazoline, substituted thiophene, pyridothiophene and quinazoline fused with substituted thiophene, pyridothiophene, quinazoline were synthesized using ionic liquid and DMSO.…”

QSAR and docking studies on Triazole Benzene Sulfonamides with human Carbonic anhydrase IX inhibitory activity

“…With reference to QSAR methodology for carbonic anhydrase inhibitors, topoisomerase inhibitors, anti‐hyperlipidemic activity, and TMP kinase inhibitors, we here report in detail a QSAR study using “QSARINS” for carbonic anhydrase IX inhibitors. In the present study, the dataset series of triazole benzene sulphonamides derivatives as inhibitors of carbonic anhydrase IX were taken from PK Sharma et al The dataset was subjected to the software for predicting the role of substituent on biological activity by generating efficient models, which are capable of estimating bioactivities of newly designed compounds with extensive parameters available within the software.…”

Docking study of novel antihyperlipidemic thieno[2,3-d]pyrimidine; LM-1554, with some molecular targets related to hyperlipidemia - an investigation into its mechanism of action

“…Drugs used as reference standards in these studies were gemfibrozil, clofibrate, riboflavin tetrabutyrate, ezetimibe. Further, the acute and chronic toxicity studies of this compound indicated it to be considerably safe with high LD 50 values (Shishoo et al 1990, 1981, 1996; Jain et al 2011; Arya 1985; Kathiravan et al 2007).

Figure 1 LM-1554- The title compound.

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“…QSAR studies undertaken on its analogs revealed the electronic parameter to be positively contributing to the antihyperlipidemic activity of these compounds. Electron withdrawing groups (EWG) attached at the 2-methyl substituent of these compounds, enhanced the activity (Shishoo et al 1996; Kathiravan et al 2007). All these interesting observations aroused our interest to probe into the pharmacodynamics of this compound.…”