Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones

Abstract

The present paper describes the application of modern combinatorial and microwave assisted techniques for the lead discovery and optimization of novel non-nucleoside HIV-1-RT inhibitors. Starting from the parallel solid phase synthesis of highly substituted pyrimidinone derivatives, compound 12c was identified as interesting lead compound for further structure optimizations. The generation and screening of a small virtual combinatorial library led to the optimization of the lead structure 12c to give highly active derivatives (against HIV1-RT wild-type and mutant strains) in the nanomolar range. Moreover, a straightforward three-step parallel solution phase approach was developed for the generation of a small library of novel 4-dialkylamino-2-methylsulfonyl-6-vinylpyrimidines which were obtained in high yield after a simple ethyl acetate extraction with no need of further purification. Surprisingly, some of these derivatives showed a new competitive inhibition of HIV1-RT never reported in the literature for this class of compounds. Molecular modeling calculations were also performed to investigate the binding mode of all synthesized compounds onto the non-nucleoside reverse transcriptase inhibitor binding site and to rationalize the relationships between their chemical structure and activity.

A new entrant in ketene family: Generation of 2‐(3‐Oxo‐allyl)‐isoindole‐1,3‐dione and their [4+2] Cycloadditions with 1,3‐Diazabuta‐1,3‐dienes

“…On the other hand, the discovery of various heterocyclic scaffolds and the development of biologically significant fused pyrimidinone derivatives, make use of functionalized pyrimidinones as synthetically useful organic synthons and templates. [14,15] Additionally, functionalized fused pyrimidinones at different locations, particularly fused at C-5 and C-6 positions, [16] have demonstrated selective anticancer, [17] antitubercular, [18] antifungal, [19] antipsychotic, [20] antiherpetic, [21] anesthetic, [21] anti-allergic, [21] antihypertensive, [21] and antimicrobial properties, [22] highlighting the value of this moiety as a class of medicines with broad therapeutic index. Some examples of pyrimidinones and their derivatives showing biological applications are given in Figure 1.…”

One‐Pot Synthesis of Furano and Pyrano Pyrimidinones (Thiones) by Using Zn‐Al−Cu@Poly Triazine‐Thiourea‐Sulfonamide‐SO3H Nanocatalyst

“…In addition, some other significant antifungal, anti-HIV, antimalarial, analgesic, and analgesic properties have been mentioned for these molecules. [2][3][4][5][6][7][8] Pyrimidine sulfonamide derivatives of the general structure 1 and also 4,5,6-trisubstituted furo [2,3-d]pyrimidin-4-amines 2 as ACK1 (Activated Cdc42-associated tyrosine Kinase 1) inhibitors (Scheme 1) are among the major molecules considered for this purpose. [9] According to recent studies, ACK1 can be regarded as a potential target to develop anti-cancer therapeutics.…”

Poly(N-bromo-N-ethyl-benzene-1,3-disulfonamide) and N,N,N′,N′-tetrabromobenzene-1,3-disulfonamide as new efficient reagents for one-pot synthesis of furano and pyrano pyrimidinones (thiones)

“…They have antimalarial, antifungal, analgesics, anti-HIV and herbicidal properties in some cases. [3][4][5][6][7][8][9] For example, some pyrimidine sulfonamide derivatives of the general structure 1 (Scheme 1) have been developed as powerful herbicides. 10 Several 4,5,6-trisubstituted furo [2,3-d] pyrimidin-4-amines 2 (Scheme 1) have been detected as ACK1 (Activated Cdc42-associated tyrosine Kinase 1) inhibitors.…”