Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design

Meanwell, Nicholas A.

doi:10.1021/jm1013693

Cited by 2,376 publications

(1,421 citation statements)

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“…Comparison with the K i of molecule 9 (K i 210 nM) suggests that the tetrazole added about 3 kcal∕mol of affinity, improving the K i 170-fold in compound 4 and 250-fold in the pyridine derivative 5. Tetrazoles are common bioisosteres of carboxylates and often have better bioavailability (28,35). Although they are not unprecedented in β-lactam antibiotics (e.g., cefazolin), boronic acid inhibitors of β-lactamases have not yet exploited this chemotype in this region of the active site.…”

Section: Discussionmentioning

confidence: 99%

Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

Eidam¹,

Romagnoli

Dalmasso

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Fragment-based design was used to guide derivatization of a lead series of β-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K i of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with β-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome β-lactamase-based resistance, a key clinical challenge.antibiotic resistance | antimicrobial | drug discovery | structure-based | boronic acid

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Section: Discussionmentioning

confidence: 99%

Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

Eidam¹,

Romagnoli

Dalmasso

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Considering that tetrazoles are carboxylic acid bioisosteres that often exhibit high bioactivities, 26 the conversion of N-cyano sulfoximine 3 into tetrazole 7 was studied. 27 By using a combination of NaN 3 and ZnBr 2 in methanolwater, formation of the heterocycle proceeded smoothly, leading to N-(1H)-tetrazole methyl 4-pentafluorosulfanylphenyl sulfoximine (7) in 62% yield (Scheme 2).…”

Section: Scheme 2 Derivatizations Of Nh-sulfoximine 4 and Conversionmentioning

confidence: 99%

Methyl 4-Pentafluorosulfanylphenyl Sulfoximines

Hendriks

Reball

Bolm

2014

Synlett

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“…They are informed that the phenol may be good for potency, but it is a group with susceptibility to rapid metabolism, so it would be prudent to prepare some bio-isosteres of the phenol. 20,21 Thus, by examining the fit of a set of heterocyclic analogues in the enzyme active site, clogP values and using the Rule of Five, the students plan to make further target compounds (6) that combine the best amine and heterocyclic groups ( Figure 1). …”

Section: Course Description: Principles Of Medicinal Chemistry Projementioning

confidence: 99%