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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).

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According to WHO reports, Cancer is the second leading cause of death worldwide and is responsible for an estimated 9.6 million deaths in 2018. Breast cancer accounted for 2.09 million cases in the year 2018. Carbonic anhydrases are involved in lowering tumor pH by converting carbon dioxide and water to carbonic acid. It is known that transcription of carbonic anhydrase IX (CA IX) is activated by hypoxia and suppressed in normoxia. 4-Hydroxy-3-(3-(phenyl ureido) benzene sulfonamides as SLC-0111 is currently in clinical trials for CA-IX inhibition activity in hypoxic tumors. One of the rational and successful methods in drug design is Quantitative structure-activity relationship (QSAR), playing a key role in optimizing leads and thereby improving their biological activity. The aim of this work is to design better leads for carbonic anhydrase IX inhibition, a major hypoxic target for breast cancer.

Fused pyrimidine derivatives R 0515Synthesis and Antihyperlipidemic Activity of Some Novel Condensed 2-Chloroalkyl-4-chloro/hydroxy-5,6-disubstituted Pyrimidines. -The new compounds (IV) exhibit much superior antihyperlipidemic activity compared to their known 4-hydroxy analogues. They show good ability to reduce total cholesterol and derivative (IVb) exhibits better reduction of serum triglycerides. A 3D QSAR study is also performed to delineate the effect of the substituents at 5 and 6 position on the antihyperlipidemic activity of intermediates (III). -(KATHIRAVAN, M. K.; SHISHOO, C. J.; KUMAR, K. G.; ROY, S. K.; MAHADIK, K. R.; KADAM, S. S.; JAIN*, K. S.; Arzneim.-Forsch. 57 (2007) 9, 599-606; Sinhgad Coll. Pharm., Pune 411 041, India; Eng.) -H. Haber 04-174

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