Practical Synthesis and Application of Halogen-Doped Pyrrole Building Blocks.

Andrej Emanuel Cotman,Daniela Secci,Federica Fulgheri,Anamarija Zega,Lucija Peterlin Mašič,Thomas Guérin,Ivana Kovačević,Maša Sterle,Nace Zidar,Tihomir Tomašič,Danijel Kikelj,Martina Durcik,Štefan Možina,Janez Ilaš,Frédéric R Leroux,Gilles Hanquet,Davide Benedetto Tiz

doi:10.1021/acsomega.1c00331

Abstract

A practical access to four new halogen-substituted pyrrole building blocks was realized in two to five synthetic steps from commercially available starting materials. The target compounds were prepared on a 50 mg to 1 g scale, and their conversion to nanomolar inhibitors of bacterial DNA gyrase B was demonstrated for three of the prepared building blocks to showcase the usefulness of such chemical motifs in medicinal chemistry.

Highlights

Halogen-substituted pyrrole-2-carboxamide is an integral molecular fragment of bioactive marine natural products as well as natural and synthetic anti-infectives (Figure 1)
During our ongoing research in the field of dual bacterial DNA gyrase/topoisomerase IV inhibitors,[9−15] a promising hit compound 1 (Figure 2) was identified, displaying low particular, mono- and dibromopyrrole-2-carboxamide are found in oroidin[1] and hymenidin,[2] which are postulated precursors for structurally diverse mono- and oligomeric secondary metabolites involved in the chemical defense of Agelas marine sponges
3,4dichloro-5-methyl-1H-pyrrole-2-carboxamide is a molecular fragment of natural[5,6] and synthetic[7] antibacterials, crucial for binding to the active site of bacterial topoisomerases, and the 3-fluoro-1H-pyrrole-2-carboxamide moiety is found in promising preclinical candidates, active against hepatitis B virus (Figure 1).[8] nanomolar inhibition of the target enzymes and broadspectrum activity against gram-positive bacterial strains.[16]

Summary

INTRODUCTION

Halogen-substituted pyrrole-2-carboxamide is an integral molecular fragment of bioactive marine natural products as well as natural and synthetic anti-infectives (Figure 1). A representative compound ageliferin[3] features a complex multichiral scaffold.[4] 3,4dichloro-5-methyl-1H-pyrrole-2-carboxamide is a molecular fragment of natural[5,6] and synthetic[7] antibacterials, crucial for binding to the active site of bacterial topoisomerases, and the 3-fluoro-1H-pyrrole-2-carboxamide moiety is found in promising preclinical candidates, active against hepatitis B virus (Figure 1).[8] nanomolar inhibition of the target enzymes and broadspectrum activity against gram-positive bacterial strains.[16] Due to the compound’s high lipophilicity, its more polar analogues 2−5 were designed by varying the 3,4-dichloro-5methyl-1H-pyrrole moiety, envisioning improved physical properties (c log P was calculated by ChemDraw) of the analogues while retaining the on-target activity (Figure 2). The amide bond of the target compounds can be formed using pyrrole-2-carbonyl chloride or 2-trichloroacetylpyrrole; either would be an acceptable option

RESULTS AND DISCUSSION

CONCLUSIONS

EXPERIMENTAL SECTION

■ ACKNOWLEDGMENTS

■ REFERENCES