The role of aldose reductase (ALR2) in causing diabetic complications is well-studied, with overactivity of ALR2 in the hyperglycemic state leading to an accumulation of intracellular sorbitol, ...depletion of cytoplasmic NADPH and oxidative stress and causing a variety of different conditions including retinopathy, nephropathy, neuropathy and cardiovascular disorders. While previous efforts have sought to develop inhibitors of this enzyme in order to combat diabetic complications, non-selective inhibition of both ALR2 and the homologous enzyme aldehyde reductase (ALR1) has led to poor toxicity profiles, with no drugs targeting ALR2 currently approved for therapeutic use in the Western world. In the current study, we have synthesized a series of N-substituted thiosemicarbazones with added phenolic moieties, of which compound 3m displayed strong and selective ALR2 inhibitory activity in vitro (IC
1.18 µM) as well as promising antioxidant activity (75.95% free radical scavenging activity). The target binding modes of 3m were studied via molecular docking studies and stable interactions with ALR2 were inferred through molecular dynamics simulations. We thus report the N-substituted thiosemicarbazones as promising drug candidates for selective inhibition of ALR2 and possible treatment of diabetic complications.
The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) plays an important role in viral replication and transcription and received great attention as a vital target ...for drug/peptide development. Therapeutic agents such as small‐molecule drugs or peptides that interact with the Cys–His present in the catalytic site of Mpro are an efficient way to inhibit the protease. Although several emergency‐approved vaccines showed good efficacy and drastically dropped the infection rate, evolving variants are still infecting and killing millions of people globally. While a small‐molecule drug (Paxlovid) received emergency approval, small‐molecule drugs have low target specificity and higher toxicity. Besides small‐molecule drugs, peptide therapeutics are thus gaining increasing popularity as they are easy to synthesize and highly selective and have limited side effects. In this study, we investigated the therapeutic value of 67 peptides targeting Mpro using molecular docking. Subsequently, molecular dynamics (MD) simulations were implemented on eight protein–peptide complexes to obtain molecular‐level information on the interaction between these peptides and the Mpro active site, which revealed that temporin L, indolicidin, and lymphocytic choriomeningitis virus (LCMV) GP1 are the best candidates in terms of stability, interaction, and structural compactness. These peptides were synthesized using the solid‐phase peptide synthesis protocol, purified by reversed‐phase high‐performance liquid chromatography (RP‐HPLC), and authenticated by mass spectrometry (MS). The in vitro fluorometric Mpro activity assay was used to validate the computational results, where temporin L and indolicidin were observed to be very active against SARS‐CoV‐2 Mpro with IC50 values of 38.80 and 87.23 μM, respectively. A liquid chromatography–MS (LC–MS) assay was developed, and the IC50 value of temporin L was measured at 23.8 μM. The solution‐state nuclear magnetic resonance (NMR) structure of temporin L was determined in the absence of sodium dodecyl sulfate (SDS) micelles and was compared to previous temporin structures. This combined investigation provides critical insights and assists us to further develop peptide inhibitors of SARS‐CoV‐2 Mpro through structural guided investigation.
The therapeutic value of 67 peptides targeting the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) main protease (Mpro) was investigated using molecular docking. Molecular dynamics simulations on eight protein–peptide complexes revealed that temporin L, indolicidin, and lymphocytic choriomeningitis virus (LCMV) GP1 are the best candidates in terms of stability, interaction, and structural compactness.
Two new epimeric bibenzylated monoterpenes machaerifurogerol (
) and 5-
-machaerifurogerol (
), and four known isoflavonoids (+)-vestitol (
), 7-
-methylvestitol (
), (+)-medicarpin (
), and ...3,8-dihydroxy-9-methoxypterocarpan (
) were isolated from
Pers. This plant was previously assigned as
Spruce, from which machaeriols A-D (
-
) and machaeridiols A-C (
-
) were reported, and all were then re-isolated, except the minor compound
, for a comprehensive antimicrobial activity evaluation. Structures of the isolated compounds were determined by full NMR and mass spectroscopic data. Among the isolated compounds, the mixture
+
was the most active with an MIC value of 1.25 μg/mL against methicillin-resistant
(MRSA) strains BAA 1696, -1708, -1717, -33591, and vancomycin-resistant
(VRE 700221) and
.
(VRE 51299) and vancomycin-sensitive
(VSE 29212). Compounds
-
and
-
were found to be more potent against MRSA 1708, and
,
, and
against VRE 700221, than the drug control ciprofloxacin and vancomycin. A combination study using an in vitro Checkerboard method was carried out for machaeriols (
or
) and machaeridiols (
or
), which exhibited a strong synergistic activity of
+
(MIC 0.156 and 0.625 µg/mL), with >32- and >8-fold reduction of MIC's, compared to
, against MRSA 1708 and -1717, respectively. In the presence of sub-inhibitory concentrations on polymyxin B nonapeptide (PMBN), compounds
+
,
,
, and
showed activity in the range of 0.5-8 µg/mL for two strains of
, 2-16 µg/mL against
PAO1, and 2 µg/mL against
NCTC 12923, but were inactive (MIC > 64 µg/mL) against the two isolates of
.
C5-acylaminomethyl part of oxazolidinone antibiotics has a very restrictive Structure Activity Relationship (SAR). Only lipophilic and smaller substituents are tolerated at this position while polar ...and aromatic substitutions result in significant reduction in antimicrobial activity.
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Antimicrobial resistance and lack of new antibiotics to treat multidrug-resistant (MDR) bacteria is a significant public health problem. There is a discovery void and the pipeline of new classes of antibiotics in clinical development is almost empty. Therefore, it is important to understand the structure activity relationships (SAR) of current chemical classes as that can help the drug discovery community in their efforts to develop new antibiotics by modifying existing antibiotic classes. We studied the SAR of the C5-acylaminomethyl moiety of the linezolid, an oxazolidinone antibiotic, by synthesizing 25 compounds containing various aromatic, heteroaromatic and aliphatic substitutions. Our findings suggest that this position is highly important for the function of this antibiotic class, since only smaller non-polar fragments are tolerated at this position while larger and polar ones lead to a decrease in activity compared to linezolid. Our findings have led us to construct a structure activity relationship, around the C5-acylaminomethyl moiety of linezolid, that provides valuable insight into the function of the oxazolidinone class of antibiotics.
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•A new series of Sulphamethazine and Sulphamethoxazole (3a-q) was synthesized.•Probed the compounds (3a-q) as urease Inhibitors.•SAR revealed that halogen and hydroxy group are ...critical for enzyme inhibition.•In silico molecular docking was carried out to study putative binding sites.•ADME studies were carried out to determine toxicity.
In the current study, a novel series of Schiff base derivatives of (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (3a-3f) and (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (3g-3q) were synthesize. The structures of synthetic compounds were elucidated by various spectroscopic techniques such as FTIR, NMR and spectrometric HRMS analysis. Synthetic derivatives were evaluated for their Jack Bean urease inhibitory activity using established in-vitro assay. It is worth mentioning here that most of our derivatives of both series displayed moderate to strong inhibitory activity, ranging between IC50 = 2.48 ± 0.78 µM and 35.63 ± 1.26 µM, as compared to standard thiourea (IC50 = 20.03 ± 2.03 µM). Further, structure activity relationship studies suggest that the presence of halogen at ortho and para positions on the aryl ring in (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide derivatives and hydroxy and halogen in (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide derivatives increased the urease inhibitory activity. Furthermore, molecular docking studies were carried out in order to investigate the binding mode of this class of compounds to urease. In order to evaluate drug likeness of compounds ADME evaluation was done, and the synthesized compounds were found to be non-toxic and present passive gastrointestinal absorption. The data suggests the synthesized sulphamethazine and sulphamethoxazole derivatives can serve as a novel scaffold to inhibit urease.
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Melting points for new drugs are reported in regulatory documents, e.g. investigational brochures, and frequently in published research; however, the authors do not typically consider ...that heat-induced degradation can affect the melting point measurement. Applying a single heating rate is not adequate, and thus many melting points in the literature and regulatory documentation are not valid. Our aim was to validate a five-stage approach for the melting point measurement of heat-sensitive drugs. These stages are; (1) observe melting; (2) record mass loss; (3) measure melting points at different heating rates; (4) characterise degradation and (5) test for potential isomerisation. Applying this approach to pilocarpine HCl illustrated the sensitivity of a melting point to thermal degradation. Due to salt disproportionation & loss of HCl gas, pilocarpine’s melting point decreased by 14 °C when the heating rate was lowered from 20 to 1 °C/min. Epimerization occurred before melting was reached. Increasing the heating rate diminished disproportionation; however, this did not remove epimerization. Thus, the melting point of pilocarpine HCl of 205.5 ± 0.4 °C measured at 20 °C/min represents the melt of a racemic mixture containing inactive isopilocarpine. Heating above the melting point accelerated degradation, a rate of 5 °C/min recovered just 38 ± 1% of pilocarpine. Such data predicted a shelf-life of 6.6 years. Pilocarpine successfully validated the multistage approach by providing new knowledge concerning its thermal stability. Our 5-stage approach must be applied to all new drugs especially if their formulation requires heat. For example, thermal stability is an infrequently considered pre-requisite in the emerging field of 3D printing.
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•A series of coumarin-based thiosemicarbazone derivatives was synthesized.•The synthesized compounds were investigated for their enzyme inhibition potential against ALR1 and ...ALR2.•Among all the compounds, 3n was the most promising inhibitor showing selectivity towards Aldose reductase (ALR2).•Molecular docking studies and molecular dynamic simulations were also carried out for compound 3n.
The over expression of aldose reductase (ALR2) in the state of hyperglycemia causes the conversion of glucose into sorbitol and initiates polyol pathway. Accumulation of sorbitol in insulin insensitive tissue like peripheral nerves, glomerulus and eyes, induces diabetic complications like neuropathy, nephropathy and retinopathy. For the treatment of diabetic complications, the inhibition of aldose reductase (ALR2) is a promising approach. A series of coumarin-based thiosemicarbazone derivatives was synthesized as potential inhibitor of aldose reductase. Compound N-(2-fluorophenyl)-2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)hydrazinecarbiothioamide (3n) was found to be the most promising inhibitor of ALR2 with an IC50 in micromolar range (2.07 µM) and high selectivity, relative to ALR1. The crystal structure of ALR2 complexed with 3n explored the types of interaction pattern which further demonstrated its high affinity. Compound 3n has excellent lead-likeness, underlined by its physicochemical parameters, and can be considered as a likely prospect for further structural optimization to get a drugable molecule.
Diabetic complications are associated with overexpression of aldose reductase, an enzyme that catalyzes the first step of the polyol pathway. Osmotic stress in the hyperglycemic state is linked with ...the intracellular accumulation of sorbitol along with the depletion of NADPH and eventually leads to oxidative stress via formation of reactive oxygen species and advanced glycation end products (AGEs). These kinds of mechanisms cause the development of various diabetic complications including neuropathy, nephropathy, retinopathy, and atherosclerotic plaque formation. Various aldose reductase inhibitors have been developed to date for the treatment of diabetic complications, but all have failed in different stages of clinical trials due to toxicity and poor pharmacokinetic profiles. This toxicity is rooted in a nonselective inhibition of both ALR2 and ALR1, homologous enzymes involved in the metabolism of toxic aldehydes such as methylglyoxal and 3-oxyglucosazone. In the present study, we developed a series of thiosemicarbazone derivatives as selective inhibitors of ALR2 with both antioxidant and antiglycation potential. Among the synthesized compounds, 3c exhibited strong and selective inhibition of ALR2 (IC50 1.42 μM) along with good antioxidant and antiglycative properties. The binding mode of 3c was assessed through molecular docking and cluster analysis via MD simulations, while in silico ADME evaluation studies predicted the compounds’ druglike properties. Therefore, we report 3c as a drug candidate with promising antioxidant and antiglycative properties that may be useful for the treatment of diabetic complications through selective inhibition of ALR2.
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