The synthesis of amide bonds is one of the most frequently performed reactions in pharmaceutical synthesis, but the requirement for stoichiometric quantities of coupling agents and activated substrates in established methods has prompted interest in biocatalytic alternatives. Amide Bond Synthetases (ABSs) actively catalyze both the ATP-dependent adenylation of carboxylic acid substrates and their subsequent amidation using an amine nucleophile, both within the active site of the enzyme, enabling the use of only a small excess of the amine partner. We have assessed the ability of an ABS from Streptoalloteichus hindustanus (ShABS) to couple a range of carboxylic acid substrates and amines to form amine products. ShABS displayed superior activity to a previously studied ABS, McbA, and a remarkable complementary substrate specificity that included the enantioselective formation of a library of amides from racemic acid and amine coupling partners. The X-ray crystallographic structure of ShABS has permitted mutational mapping of the carboxylic acid and amine binding sites, revealing key roles for L207 and F246 in determining the enantioselectivity of the enzyme with respect to chiral acid and amine substrates. ShABS was applied to the synthesis of pharmaceutical amides, including ilepcimide, lazabemide, trimethobenzamide, and cinepazide, the last with 99% conversion and 95% isolated yield. These findings provide a blueprint for enabling a contemporary pharmaceutical synthesis of one of the most significant classes of small molecule drugs using biocatalysis.

19 Dec 2023·ACS Omega

Development of a New Class of Monoamine Oxidase-B Inhibitors by Fine-Tuning the Halogens on the Acylhydrazones

Article

Author: Ebrahim, Hasnaa Ali ; Manoharan, Amritha ; Mathew, Bijo ; Narayanan, Anishma Payyappilliparambil ; Mary Zachariah, Subin ; Kumar, Sunil ; Lee, Jiseong ; Jauhari, Reenoo ; Ghoneim, Mohammed M ; Abdelgawad, Mohamed A ; Kim, Hoon ; Jayan, Jayalakshmi

A total of 14 acyl hydrazine derivatives (ACH1-ACH14) were developed and examined for their ability to block monoamine oxidase (MAO). Thirteen analogues showed stronger inhibition potency against MAO-B than MAO-A. With a half-maximum inhibitory concentration of 0.14 μM, ACH10 demonstrated the strongest inhibitory activity against MAO-B, followed by ACH14, ACH13, ACH8, and ACH3 (IC₅₀ = 0.15, 0.18, 0.20, and 0.22 μM, respectively). Structure-activity relationships suggested that the inhibition effect on MAO-B resulted from the combination of halogen substituents of the A- and/or B-rings. This series concluded that when -F was substituted to the B-ring, MAO-B inhibitory activities were high, except for ACH6. In the inhibition kinetics study, the compounds ACH10 and ACH14 were identified as competitive inhibitors, with K_i values of 0.097 ± 0.0021 and 0.10 ± 0.038 μM, respectively. In a reversibility experiment using the dialysis methods, ACH10 and ACH14 showed effective recoveries of MAO-B inhibition as much as lazabemide, a reversible reference. These experiments proposed that ACH10 and ACH14 were efficient, reversible competitive MAO-B inhibitors. In addition, the lead molecules showed good blood-brain barrier permeation with the PAMPA method. The molecular docking and molecular dynamics simulation study confirmed that the hit compound ACH10 can form a stable protein-ligand complex by forming a hydrogen bond with the NH atom in the hydrazide group of the compound.

01 Aug 2023·Chemical biology & drug design

Exploration of a new class of monoamine oxidase B inhibitors by assembling benzyloxy pharmacophore on halogenated chalcones.

Article

Author: Oh, Jong Min ; Sudevan, Sachithra Thazhathuveedu ; Rangarajan, T M ; Trisciuzzi, Daniela ; Mathew, Bijo ; Singh, Ashutosh Kumar ; Kim, Seong-Min ; Ghoneim, Mohammed M ; Abdelgawad, Mohamed A ; Kim, Hoon ; Kumar, Sunil ; Nicolotti, Orazio

Eight derivatives of benzyloxy-derived halogenated chalcones (BB1-BB8) were synthesized and tested for their ability to inhibit monoamine oxidases (MAOs). MAO-A was less efficiently inhibited by all compounds than MAO-B. Additionally, the majority of the compounds displayed significant MAO-B inhibitory activities at 1 μM with residual activities of less than 50%. With an IC₅₀ value of 0.062 μM, compound BB4 was the most effective in inhibiting MAO-B, followed by compound BB2 (IC₅₀ = 0.093 μM). The lead molecules showed good activity than the reference MAO-B inhibitors (Lazabemide IC₅₀ = 0.11 μM and Pargyline Pargyline IC₅₀ = 0.14). The high selectivity index (SI) values for MAO-B were observed in compounds BB2 and BB4 (430.108 and 645.161, respectively). Kinetics and reversibility experiments revealed that BB2 and BB4 were reversible competitive MAO-B inhibitors with K_i values of 0.030 ± 0.014 and 0.011 ± 0.005 μM, respectively. Swiss target prediction confirmed the high probability in the targets of MAO-B for both compounds. Hypothetical binding mode revealed that the BB2 or BB4 is similarly oriented to the binding cavity of MAO-B. Based on the modelling results, BB4 showed a stable confirmation during the dynamic simulation. From these results, it was concluded that BB2 and BB4 were potent selective reversible MAO-B inhibitors and they can be considered drug candidates for treating related neurodegenerative diseases such as Parkinson's disease.

100 Deals associated with Lazabemide Hydrochloride

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KEGG	Wiki	ATC	Drug Bank
D01097	Lazabemide Hydrochloride	-	-

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	NDA/BLA	-	F. Hoffmann-La Roche Ltd.	-
Alzheimer Disease	NDA/BLA	JP	-	-
Alzheimer Disease	NDA/BLA	-	-	-
Parkinson Disease	NDA/BLA	JP	-	-

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