Pyrimidine: A promising scaffold for optimization to develop the inhibitors of ABC transporters

Scaffold fragmentation and substructure hopping reveal potential, robustness, and limits of computer-aided pattern analysis (C@PA)

“…The omnipresent substructures pyrimidine [15] , [17] and pyridine [15] must be seen in a different light, as these cannot be regarded on their own as indicators for multitarget ABCB1, ABCC1, and ABCG2 inhibition due to their ubiquitousness. However, our results indicate that these substructures have generally a positive impact on broad-spectrum ABCB1, ABCC1, and ABCG2 inhibition, depending on the composition of and combination with other substructures.…”

“…Unfortunately, only a small fraction of the 49 existing ABC transporters can be considered as well-studied, in particular ABCB1 [8] , [14] , [15] , [16] , [17] , [18] , [19] , ABCB11 [20] , [21] , [22] , ABCC1 [1] , [4] , [14] , [15] , [17] , [23] , [24] , and ABCG2 [14] , [15] , [17] , [25] . Less-studied ABC transporters that have found much less attention are ABCC2, ABCC4–5, and ABCC10 [1] , [4] , [14] , [24] , [26] , as well as – to a lesser extend – ABCA1 [27] , [28] , [29] , [30] , ABCB4 [14] , ABCC3 [1] , [4] , [14] , [24] , as well as ABCC7–9 and ABCC11 [1] , [4] , [31] , [32] .…”

“…As a logical consequence, the number of synthetic approaches to gain novel lead structures and potent modulators of ABC transporters is also very unequally distributed amongst the ABC transport proteins, and very scarce for under-studied ABC transporters. While many hundreds of small-molecule modulators of ABCB1 [14] , [15] , [16] , [17] , [18] , [19] , ABCC1 [1] , [4] , [14] , [15] , [17] , [23] , [24] , and ABCG2 [14] , [15] , [17] , [25] exist, synthetic approaches to target other ABC transporters have barely been reported. Rare exceptions are, for example, ABCC4 [33] , [34] , ABCC8 [35] , or ABCC10 [36] .…”

One‐potandtwo‐potmethods for chalcone derived pyrimidines synthesis and applications

“…Many studies and reviews on pyrimidines are mainly reported on the synthesis and the biological applications, [139][140][141][142][143][144][145][146][147][148][149] organic light-emitting diodes, [150] and corrosion inhibition. [151] Herein, we discuss comprehensive synthetic methods via one-pot and two-pot for the synthesis of pyrimidine derivatives from chalcone, a highly stable, cheap, commercially available starting material.…”

Quinolin-2-one-pyrimidine Hybrids Acting as Potent Reversal Agents on the P-gp-mediated Multidrug Resistance: Insights into Structure-activity Relationships and the Binding Mode

“…The importance of the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety in the highly effective third-generation P-gp inhibitors, tariquidar, which also bears an isoquinoline group, elacridar, HM30181, WK-X-34 11,12 and their derivatives, some containing aromatic amide 2,12 , as well as the presence of an aminopyrimidine moiety in the P-gp inhibitor, imatinib 13 , and the promising MDR reversal activity of the multi-substituted or fused pyrimidine scaffold 14 , encouraged us to search for potential P-gp inhibitors in a library of new quinolin-2-one-pyrimidine hybrids 15 .…”