Guanidines from ‘toxic substances’ to compounds with multiple biological applications – Detailed outlook on synthetic procedures employed for the synthesis of guanidines

A review of phenformin, metformin, and imeglimin

“…Essentially, the simplest unit in the three molecules is the guanidine polyamine group (Figure ). This unit is both biologically multiactive and synthetically versatile that could be readily derivatized via the circled N ‐atoms (Figure ; Katritzky, Tala, & Singh, ; Tahir, Badshah, & Hussain, ). The biguanide core, which is a merger of two guanidine units, is capable of eliciting a myriad of pharmacological effects via hydrogen bonding and ionic interactions with its receptors, at physiologic pH (Langmaier, Pizl, Samec, & Zalis, ; Saczewski & Balewski, ; Tahir et al, ).…”

“…This unit is both biologically multiactive and synthetically versatile that could be readily derivatized via the circled N ‐atoms (Figure ; Katritzky, Tala, & Singh, ; Tahir, Badshah, & Hussain, ). The biguanide core, which is a merger of two guanidine units, is capable of eliciting a myriad of pharmacological effects via hydrogen bonding and ionic interactions with its receptors, at physiologic pH (Langmaier, Pizl, Samec, & Zalis, ; Saczewski & Balewski, ; Tahir et al, ). Although hydrogen bonding also contributes to the hydrophilic nature of biguanides, their characteristically high pKa (>12) leads to: mono‐ or di‐protonation at physiological pH and N ‐atom reactions with acids like HCl to make highly water soluble salts (Langmaier et al, ).…”

Acyl guanidine functional poly(2‐oxazoline)s as reactive intermediates and stimuli‐responsive materials

“…This partial protonation lowers their overall polarity (Log P octanol/water ), which may be beneficial for their biodistribution, as highly polar guanidines suffer from poor membrane permeability . Hence, their application as bioisosters of guanidines received attention in medicinal chemistry to increase uptake and improve biodistribution, thereby improving the efficacy of many guanidine‐based drugs . These interesting features have led us to explore the utilization of methyl ester functional PAOx for the acylation of guanidines.…”

One-pot synthesis of diverseN,N′-disubstituted guanidines fromN-chlorophthalimide, isocyanides and aminesvia N-phthaloyl-guanidines

“…8 S-Oxidized thiourea derivatives 9 and guanylating agents 10 (such as S-methylisothioureas, pyrazole-1-carboximidamide and its derivatives, or triflyl guanidines) are also commonly employed. Beyond the well-known 11 and recently 12 developed approaches, a few isocyanide-based procedures have also been established, albeit each method exclusively affords N,N′,N″-substituted guanidines. 13 Looking at the synthetic toolbox for the assembly of N,N′-disubstituted guanidines, N-protected S-methylisothioureas are often used as starting materials; however, the techniques available for the derivatization of isothioureas lack the achievable diversity (Scheme 1a).…”