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Medicinal Chemistry Research
Journal Prestige (SJR): 0.422  Citation Impact (citeScore): 2 Number of Followers: 12  Hybrid journal (It can contain Open Access articles)ISSN (Print) 1054-2523 - ISSN (Online) 1554-8120 Published by Springer-Verlag  [2626 journals]
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- In honor of Professor Robert Vince on the occasion of his 80th birthday
- PubDate: 2021-01-23
- PubDate: 2021-01-23
- Synthesis and in vitro evaluation of triphenylphosphonium derivatives of
acetylsalicylic and salicylic acids: structure-dependent interactions with
cancer cells, bacteria, and mitochondria- Abstract: Abstract Salicylic acid (SA) remains one of the most fruitful natural compounds to generate drug molecules with versatile activities. In this study, effective synthesis of SA and acetylsalicylic acid (ASA) derivatives with a carrier triphenylphoshonium (TPP) group was proposed. A series of SA and ASA conjugates linked with the TPP group via alkyl chain linker (C3-C10) was synthesized. The conjugates showed enhanced TPP-mediated cytotoxicity towards MCF-7, Caco-2, PC-3 cells in proportion to the linker length. 7e, 8e (C9), and 7f (C10) were the most active against the cancer cells with IC50 = 0.6–1.9 µM while were less toxic for HSF. Similarly, antibacterial (bactericidal) activity of the compounds against S. aureus increased with the linker elongation. The lowest MIC for SA and ASA derivatives were 4 and 1 µM, respectively. The TPP conjugates induced early linker length-dependent mitochondria depolarization and concurrent superoxide radical production in the cancer cells. The most lipophilic conjugates were found to specifically interact with ROS probe 2′,7′-dichlorofluorescin diacetate, forming mixed aggregates with the probe and inhibiting its fluorescence upon oxidation. These interactions were exploited to probe the compounds inside living cells. The results identify 7e and 7f as promising mitochondria-modulating and anticancer agents with increased cellular availability.
PubDate: 2021-01-21
- Abstract: Abstract Salicylic acid (SA) remains one of the most fruitful natural compounds to generate drug molecules with versatile activities. In this study, effective synthesis of SA and acetylsalicylic acid (ASA) derivatives with a carrier triphenylphoshonium (TPP) group was proposed. A series of SA and ASA conjugates linked with the TPP group via alkyl chain linker (C3-C10) was synthesized. The conjugates showed enhanced TPP-mediated cytotoxicity towards MCF-7, Caco-2, PC-3 cells in proportion to the linker length. 7e, 8e (C9), and 7f (C10) were the most active against the cancer cells with IC50 = 0.6–1.9 µM while were less toxic for HSF. Similarly, antibacterial (bactericidal) activity of the compounds against S. aureus increased with the linker elongation. The lowest MIC for SA and ASA derivatives were 4 and 1 µM, respectively. The TPP conjugates induced early linker length-dependent mitochondria depolarization and concurrent superoxide radical production in the cancer cells. The most lipophilic conjugates were found to specifically interact with ROS probe 2′,7′-dichlorofluorescin diacetate, forming mixed aggregates with the probe and inhibiting its fluorescence upon oxidation. These interactions were exploited to probe the compounds inside living cells. The results identify 7e and 7f as promising mitochondria-modulating and anticancer agents with increased cellular availability.
- Divalent tranylcypromine derivative as lysine-specific demethylase 1
inhibitor- Abstract: Abstract Tranylcypromine (TCP) is a useful pharmacophore for lysine-specific demethylase 1 (LSD1) inhibitors. Based on the mode of action (MOA) of TCP and structure of LSD1, divalent TCP derivatives with aliphatic and benzylic linkers were designed, synthesized, and evaluated for their LSD1 inhibitory activity, MV4-11 antiproliferative activity, and CD86 mRNA expression enhancement. All ten new compounds showed improved activity against LSD1 than TCP and GSK2879552. Several compounds with rigid aliphatic linkers demonstrated nanomolar enzymatic and cellular activities, as well as good MAO-A/B selectivity. Further supported by their significant CD86 mRNA expression enhancement effect, divalent TCP derivative can be promising lead for new LSD1 inhibitors.
PubDate: 2021-01-20
- Abstract: Abstract Tranylcypromine (TCP) is a useful pharmacophore for lysine-specific demethylase 1 (LSD1) inhibitors. Based on the mode of action (MOA) of TCP and structure of LSD1, divalent TCP derivatives with aliphatic and benzylic linkers were designed, synthesized, and evaluated for their LSD1 inhibitory activity, MV4-11 antiproliferative activity, and CD86 mRNA expression enhancement. All ten new compounds showed improved activity against LSD1 than TCP and GSK2879552. Several compounds with rigid aliphatic linkers demonstrated nanomolar enzymatic and cellular activities, as well as good MAO-A/B selectivity. Further supported by their significant CD86 mRNA expression enhancement effect, divalent TCP derivative can be promising lead for new LSD1 inhibitors.
- Tuberculosis: current scenario, drug targets, and future prospects
- Abstract: Abstract Globally recognized genetic modification with time has supported the emergence of versatile and novel featured organisms in nature, some of which can be analogized with Pandora’s box elements; like Mycobacterium sp. which has revived itself again after again in a repetitive order over decades and, gradually, contriving a red alert on the world health graph. It needs to be rectified with the motivation of new drug approval considering the pipe line moieties or, apt a choice from the existing drug genera. Although, with genetic modification and advancement Mycobacterium tuberculosis has ruined the first-line therapy in ash, it also opens up different loops and wholes to drug susceptibility. New moieties: Tiliacorinine, 2′-nortiliacorinine, tiliacorine or Cyclohexylgriselimycin raised from different sources of nature, have given another opportunity for the survival, besides, new approved drugs, like bedaquiline, delamanid, pyrifazimine, telacebec, or the under focused pharmacophores; such as diarylquinoline, quinolones, ethylurea benzimidazole, etc. are the appreciable efforts achieved. Thereupon, InhA, KatG, Clp proteases, Menaquinone, DNA gyrase, VDR Fok1, etc. are the new target sets for the drug discovery which has immense potency to generate a number of targeted molecules with effective anti-TB activity. It is a critical discussion of the TB futuristic approach including, clinical trials, repurposed drugs, pipeline motifs, natural products, upcoming drug targets from the cell wall, protein, and DNA.
PubDate: 2021-01-20
- Abstract: Abstract Globally recognized genetic modification with time has supported the emergence of versatile and novel featured organisms in nature, some of which can be analogized with Pandora’s box elements; like Mycobacterium sp. which has revived itself again after again in a repetitive order over decades and, gradually, contriving a red alert on the world health graph. It needs to be rectified with the motivation of new drug approval considering the pipe line moieties or, apt a choice from the existing drug genera. Although, with genetic modification and advancement Mycobacterium tuberculosis has ruined the first-line therapy in ash, it also opens up different loops and wholes to drug susceptibility. New moieties: Tiliacorinine, 2′-nortiliacorinine, tiliacorine or Cyclohexylgriselimycin raised from different sources of nature, have given another opportunity for the survival, besides, new approved drugs, like bedaquiline, delamanid, pyrifazimine, telacebec, or the under focused pharmacophores; such as diarylquinoline, quinolones, ethylurea benzimidazole, etc. are the appreciable efforts achieved. Thereupon, InhA, KatG, Clp proteases, Menaquinone, DNA gyrase, VDR Fok1, etc. are the new target sets for the drug discovery which has immense potency to generate a number of targeted molecules with effective anti-TB activity. It is a critical discussion of the TB futuristic approach including, clinical trials, repurposed drugs, pipeline motifs, natural products, upcoming drug targets from the cell wall, protein, and DNA.
- Novel 1-methoxyindole- and 2-alkoxyindole-based chalcones: design,
synthesis, characterization, antiproliferative activity and DNA, BSA
binding interactions- Abstract: Abstract Indole-based chalcones have been identified as interesting compounds with anticancer properties. In the present study, we report the synthesis and evaluation of new 1-methoxyindole and 2-alkoxyindole chalcone hybrids as antiproliferative agents active against colorectal carcinoma cell line. Among the 19 investigated molecules, four inhibit the proliferation of colorectal cancer cells HCT-116 with IC50 values <8 µM and display low cytotoxicity to fibroblast cell line 3T3. The UV–visible, CD and fluorescence competitive displacement assays with ethidium bromide and Hoechst 33258 performed with two active chalcones demonstrated that investigated chalcones interact with calf thymus (CT) DNA through the groove binding mode. Likewise, the quenching interaction of chalcones with bovine serum albumin (BSA) was studied in vitro under optimal physiological condition (pH = 7.4). The Stern–Volmer constant for chalcone-BSA system was found in the range of 105 M−1.
PubDate: 2021-01-16
- Abstract: Abstract Indole-based chalcones have been identified as interesting compounds with anticancer properties. In the present study, we report the synthesis and evaluation of new 1-methoxyindole and 2-alkoxyindole chalcone hybrids as antiproliferative agents active against colorectal carcinoma cell line. Among the 19 investigated molecules, four inhibit the proliferation of colorectal cancer cells HCT-116 with IC50 values <8 µM and display low cytotoxicity to fibroblast cell line 3T3. The UV–visible, CD and fluorescence competitive displacement assays with ethidium bromide and Hoechst 33258 performed with two active chalcones demonstrated that investigated chalcones interact with calf thymus (CT) DNA through the groove binding mode. Likewise, the quenching interaction of chalcones with bovine serum albumin (BSA) was studied in vitro under optimal physiological condition (pH = 7.4). The Stern–Volmer constant for chalcone-BSA system was found in the range of 105 M−1.
- γ- and δ-lactones as fumarate esters analogues and their
neuroprotective effects- Abstract: Abstract The γ-butyrolactone and δ-valerolactone structural units are present in different natural products with significant pharmacological properties. Fumaric acid ester-based drugs are used for the treatment of psoriasis and, more recently, multiple sclerosis. We synthesized different γ-butyrolactone and δ-valerolactone derivatives where the fumarate moiety is forced into a lactone ring in search of strategies to maintain the anti-inflammatory activity of fumaric acid esters limiting the side effects and enhancing the bioavailability. The structures of all synthesized compounds obtained were identified on the basis of their spectral data. The toxicity profile as well as the neuroprotective properties of the synthesized derivatives were evaluated in human neuroblastoma SH-SY5Y cell line. All tested fumaric esters presented lower cytotoxicity and higher neuroprotective properties, in comparison to dimethyl fumarate. Pre-treatment of cells with at least seven compounds for 24 h lead to a significantly neuroprotection against H2O2-induced cell damage. Our results demonstrate that SH-SY5Y cells are suitable cellular model to evaluate the neuroprotective role of fumaric acid esters, and support further evaluation of BG-12 derivatives aimed at decreasing cytotoxicity and limiting the side effects for improvement of treatments for multiple sclerosis and psoriasis.
PubDate: 2021-01-16
- Abstract: Abstract The γ-butyrolactone and δ-valerolactone structural units are present in different natural products with significant pharmacological properties. Fumaric acid ester-based drugs are used for the treatment of psoriasis and, more recently, multiple sclerosis. We synthesized different γ-butyrolactone and δ-valerolactone derivatives where the fumarate moiety is forced into a lactone ring in search of strategies to maintain the anti-inflammatory activity of fumaric acid esters limiting the side effects and enhancing the bioavailability. The structures of all synthesized compounds obtained were identified on the basis of their spectral data. The toxicity profile as well as the neuroprotective properties of the synthesized derivatives were evaluated in human neuroblastoma SH-SY5Y cell line. All tested fumaric esters presented lower cytotoxicity and higher neuroprotective properties, in comparison to dimethyl fumarate. Pre-treatment of cells with at least seven compounds for 24 h lead to a significantly neuroprotection against H2O2-induced cell damage. Our results demonstrate that SH-SY5Y cells are suitable cellular model to evaluate the neuroprotective role of fumaric acid esters, and support further evaluation of BG-12 derivatives aimed at decreasing cytotoxicity and limiting the side effects for improvement of treatments for multiple sclerosis and psoriasis.
- Development and therapeutic potential of 2-aminothiazole derivatives in
anticancer drug discovery- Abstract: Abstract Currently, the development of anticancer drug resistance is significantly restricted the clinical efficacy of the most commonly prescribed anticancer drug. Malignant disease is widely prevalent and considered to be the major challenges of this century, which concerns the medical community all over the world. Consequently, investigating small molecule antitumor agents, which could decrease drug resistance and reduce unpleasant side effect is more desirable. 2-aminothiazole scaffold has emerged as a promising scaffold in medicinal chemistry and drug discovery research. This nucleus is a fundamental part of some clinically applied anticancer drugs such as dasatinib and alpelisib. Literature survey documented that different 2-aminothiazole analogs exhibited their potent and selective nanomolar inhibitory activity against a wide range of human cancerous cell lines such as breast, leukemia, lung, colon, CNS, melanoma, ovarian, renal, and prostate. In this paper, we have reviewed the progresses and structural modification of 2-aminothiazole to pursuit potent anticancers and also highlighted in vitro activities and in silico studies. The information will useful for future innovation. Representatives of 2-aminothiazole-containing compounds classification
PubDate: 2021-01-15
- Abstract: Abstract Currently, the development of anticancer drug resistance is significantly restricted the clinical efficacy of the most commonly prescribed anticancer drug. Malignant disease is widely prevalent and considered to be the major challenges of this century, which concerns the medical community all over the world. Consequently, investigating small molecule antitumor agents, which could decrease drug resistance and reduce unpleasant side effect is more desirable. 2-aminothiazole scaffold has emerged as a promising scaffold in medicinal chemistry and drug discovery research. This nucleus is a fundamental part of some clinically applied anticancer drugs such as dasatinib and alpelisib. Literature survey documented that different 2-aminothiazole analogs exhibited their potent and selective nanomolar inhibitory activity against a wide range of human cancerous cell lines such as breast, leukemia, lung, colon, CNS, melanoma, ovarian, renal, and prostate. In this paper, we have reviewed the progresses and structural modification of 2-aminothiazole to pursuit potent anticancers and also highlighted in vitro activities and in silico studies. The information will useful for future innovation. Representatives of 2-aminothiazole-containing compounds classification
- Sulfur-containing therapeutics in the treatment of Alzheimer’s
disease- Abstract: Abstract Sulfur is widely existent in natural products and synthetic organic compounds as organosulfur, which are often associated with a multitude of biological activities. OBenzothiazole, in which benzene ring is fused to the 4,5-positions of the thiazolerganosulfur compounds continue to garner increasing amounts of attention in the field of medicinal chemistry, especially in the development of therapeutic agents for Alzheimer’s disease (AD). AD is a fatal neurodegenerative disease and the primary cause of age-related dementia posing severe societal and economic burdens. Unfortunately, there is no cure for AD. A lot of research has been conducted on sulfur-containing compounds in the context of AD due to their innate antioxidant potential and some are currently being evaluated in clinical trials. In this review, we have described emerging trends in the field, particularly the concept of multi-targeting and formulation of disease-modifying strategies. SAR, pharmacological targets, in vitro/vivo ADMET, efficacy in AD animal models, and applications in clinical trials of such sulfur compounds have also been discussed. This article provides a comprehensive review of organosulfur-based AD therapeutic agents and provides insights into their future development.
PubDate: 2021-01-15
- Abstract: Abstract Sulfur is widely existent in natural products and synthetic organic compounds as organosulfur, which are often associated with a multitude of biological activities. OBenzothiazole, in which benzene ring is fused to the 4,5-positions of the thiazolerganosulfur compounds continue to garner increasing amounts of attention in the field of medicinal chemistry, especially in the development of therapeutic agents for Alzheimer’s disease (AD). AD is a fatal neurodegenerative disease and the primary cause of age-related dementia posing severe societal and economic burdens. Unfortunately, there is no cure for AD. A lot of research has been conducted on sulfur-containing compounds in the context of AD due to their innate antioxidant potential and some are currently being evaluated in clinical trials. In this review, we have described emerging trends in the field, particularly the concept of multi-targeting and formulation of disease-modifying strategies. SAR, pharmacological targets, in vitro/vivo ADMET, efficacy in AD animal models, and applications in clinical trials of such sulfur compounds have also been discussed. This article provides a comprehensive review of organosulfur-based AD therapeutic agents and provides insights into their future development.
- Anti-inflammatory scalarane-type sesterterpenes, erectascalaranes A–B,
from the marine sponge Hyrtios erectus attenuate pro-inflammatory
cyclooxygenase-2 and 5-lipoxygenase- Abstract: Abstract Chemical investigation of demosponge Hyrtios erectus (family Thorectidae) resulted in the identification of two scalarane-type sesterterpenes, erectascalaranes A–B, which were characterized as 3-((but-35-enyloxy)methyl)-icosahydro-11-hydroxy-4,4,8,10,13-pentamethyl-20-oxochryseno[2,1-c]furan-12-yl acetate (erectascalarane A) and 3-((but-35-enyloxy)methyl)-hexadecahydro-11-hydroxy-4,4,8,10,13-pentamethylchryseno[2,1-c]furan-20(5bH)-one (erectascalarane B) using detailed spectroscopic experiments. Erectascalarane A exhibited significantly greater attenuation property against pro-inflammatory cyclooxygenase-2 (IC50 0.80 mM) than that displayed by erectascalarane B (IC50 ~ 1 mM). Erectascalarane A was found to be a potential inhibitor against 5-lipoxygenase (IC50 1.21 mM), and its activity was significantly higher than that displayed by standard anti-inflammatory agent ibuprofen (IC50 4.50 mM, p < 0.05). Greater anti-inflammatory selectivity index of erectascalarane A (1.15) than ibuprofen (0.43) also accounted for greater selectivity of the former against cyclooxygenase-2. Erectascalarane A also exhibited significantly greater antioxidant activities against oxidants (IC50 ~ 0.8 mM) than the standard α-tocopherol (IC50 > 1.5 mM). Lesser docking parameters obtained for erectascalarane A at the active site of COX-2 and greater electronic factors acquired from structure–activity analyses (topological polar surface area 82.06) were also in agreement with greater anti-inflammatory activity. Lesser steric bulk and greater electronic properties combined with lower binding energy with cyclooxygenase-2 further reinforced the significant anti-inflammatory potential of erectascalarane A.
PubDate: 2021-01-15
- Abstract: Abstract Chemical investigation of demosponge Hyrtios erectus (family Thorectidae) resulted in the identification of two scalarane-type sesterterpenes, erectascalaranes A–B, which were characterized as 3-((but-35-enyloxy)methyl)-icosahydro-11-hydroxy-4,4,8,10,13-pentamethyl-20-oxochryseno[2,1-c]furan-12-yl acetate (erectascalarane A) and 3-((but-35-enyloxy)methyl)-hexadecahydro-11-hydroxy-4,4,8,10,13-pentamethylchryseno[2,1-c]furan-20(5bH)-one (erectascalarane B) using detailed spectroscopic experiments. Erectascalarane A exhibited significantly greater attenuation property against pro-inflammatory cyclooxygenase-2 (IC50 0.80 mM) than that displayed by erectascalarane B (IC50 ~ 1 mM). Erectascalarane A was found to be a potential inhibitor against 5-lipoxygenase (IC50 1.21 mM), and its activity was significantly higher than that displayed by standard anti-inflammatory agent ibuprofen (IC50 4.50 mM, p < 0.05). Greater anti-inflammatory selectivity index of erectascalarane A (1.15) than ibuprofen (0.43) also accounted for greater selectivity of the former against cyclooxygenase-2. Erectascalarane A also exhibited significantly greater antioxidant activities against oxidants (IC50 ~ 0.8 mM) than the standard α-tocopherol (IC50 > 1.5 mM). Lesser docking parameters obtained for erectascalarane A at the active site of COX-2 and greater electronic factors acquired from structure–activity analyses (topological polar surface area 82.06) were also in agreement with greater anti-inflammatory activity. Lesser steric bulk and greater electronic properties combined with lower binding energy with cyclooxygenase-2 further reinforced the significant anti-inflammatory potential of erectascalarane A.
- Structural insights of sulfonamide-based NLRP3 inflammasome inhibitors:
design, synthesis, and biological characterization- Abstract: Abstract NLRP3 inflammasome has recently attracted much attention as a potentially druggable target to develop potential therapeutics for inflammatory and neurodegenerative disorders. In our continuing studies, structure–activity relationship studies were conducted based on a newly identified NLRP3 inhibitor, YQ-II-128, from our laboratory to understand the structural features and improve aqueous solubility. The results revealed that steric interactions at the propoxyl and amide domain of YQ-II-128 are important for the observed inhibitory potency on the NLRP3 inflammasome. The results also identified the amide domain to incorporate polar moieties to improve solubility and potentially pharmacokinetic properties. As a result, analog 10 was identified as a selective NLRP3 inhibitor with comparable potency while significantly improved aqueous solubility. Collectively, these findings strongly encourage further optmization of 10 to develop analogs with improved pharmacokinetic properties as potential NLRP3-targted therapeutics.
PubDate: 2021-01-13
- Abstract: Abstract NLRP3 inflammasome has recently attracted much attention as a potentially druggable target to develop potential therapeutics for inflammatory and neurodegenerative disorders. In our continuing studies, structure–activity relationship studies were conducted based on a newly identified NLRP3 inhibitor, YQ-II-128, from our laboratory to understand the structural features and improve aqueous solubility. The results revealed that steric interactions at the propoxyl and amide domain of YQ-II-128 are important for the observed inhibitory potency on the NLRP3 inflammasome. The results also identified the amide domain to incorporate polar moieties to improve solubility and potentially pharmacokinetic properties. As a result, analog 10 was identified as a selective NLRP3 inhibitor with comparable potency while significantly improved aqueous solubility. Collectively, these findings strongly encourage further optmization of 10 to develop analogs with improved pharmacokinetic properties as potential NLRP3-targted therapeutics.
- Design and synthesis of newer N-benzimidazol-2yl benzamide analogues as
allosteric activators of human glucokinase- Abstract: Abstract Allosteric activators of human glucokinase (GK) had revealed significant hypoglycemic effects for therapy of type-2 diabetes (T2D) in animal as well as human models. Some newer N-benzimidazol-2yl substituted benzamide analogues were prepared and assessed for activation of GK accompanied by molecular docking investigations for predicting the bonding interactions of these derivatives with the residues in allosteric site of GK protein. Amongst the derivatives synthesized, compounds 2 and 7 strongly increased catalytic action of GK (GK activation fold >2.0 in comparison to control) in vitro. The results of in-vitro testing were supported by the molecular docking investigations of these analogues with GK protein’s allosteric site residues (showed appreciable H-bond interactions with Arg63 residue of GK). Derivatives investigated in present study afforded few lead compounds for the discovery of harmless and strong allosteric GK activating compounds for treating T2D.
PubDate: 2021-01-13
- Abstract: Abstract Allosteric activators of human glucokinase (GK) had revealed significant hypoglycemic effects for therapy of type-2 diabetes (T2D) in animal as well as human models. Some newer N-benzimidazol-2yl substituted benzamide analogues were prepared and assessed for activation of GK accompanied by molecular docking investigations for predicting the bonding interactions of these derivatives with the residues in allosteric site of GK protein. Amongst the derivatives synthesized, compounds 2 and 7 strongly increased catalytic action of GK (GK activation fold >2.0 in comparison to control) in vitro. The results of in-vitro testing were supported by the molecular docking investigations of these analogues with GK protein’s allosteric site residues (showed appreciable H-bond interactions with Arg63 residue of GK). Derivatives investigated in present study afforded few lead compounds for the discovery of harmless and strong allosteric GK activating compounds for treating T2D.
- N -(2,3,4,6-tetra- O -acetyl-β- d -glucopyranosyl)thiosemicarbazones of
6-alkoxy-2-oxo-2 H -chromene-4-carbaldehydes: synthesis, evaluation of
their antibacterial, anti-MRSA, antifungal activity, and docking study- Abstract: Abstract Reaction of 6-alkoxy-2-oxo-2H-chromen-4-carbaldehydes with N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)thiosemicarbazide yielded corresponding thiosemicarbazones having 2H-chromen-2-one ring. In vitro evaluations showed that these 2H-chromen-2-one compounds exhibited remarkable antibacterial and antifungal activities against some typical bacteria and fungi. Representative compounds with MIC values of 0.78 − 1.56 μg/mL were 6c, 6g (against S. aureus), 6a, 6f (against S. epidermidis) (Gram-positive bacterial strains), 6e, 6g (against E. coli), 6b, 6e (against K. pneumoniae), and 6d–f (against S. typhimurium) (Gram-negative bacterial strains). Almost all thiosemicarbazones 6a–g had no activity against Gram-positive bacterial strain B. subtilis at these MIC values. Some compounds had strong inhibitory activity against several bacteria, such as 6b (for K. pneumoniae and S. typhimurium), 6d, 6e (for E. coli, K. pneumoniae, and S. typhimurium), 6f (for S. aureus, E. coli, and S. typhimurium), and 6g (for B. subtilis, S. aureus, E. coli, and K. pneumoniae). Some compounds had remarkable inhibitory activity against three clinical MRSA isolates with MIC values of 0.78–6.25 μg/mL. Docking study showed that compound 6g is compatible with the active site of S. aureus DNA gyrase 2XCT, which suggested that the tested compounds inhibited the synthesis of this enzyme.
PubDate: 2021-01-13
- Abstract: Abstract Reaction of 6-alkoxy-2-oxo-2H-chromen-4-carbaldehydes with N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)thiosemicarbazide yielded corresponding thiosemicarbazones having 2H-chromen-2-one ring. In vitro evaluations showed that these 2H-chromen-2-one compounds exhibited remarkable antibacterial and antifungal activities against some typical bacteria and fungi. Representative compounds with MIC values of 0.78 − 1.56 μg/mL were 6c, 6g (against S. aureus), 6a, 6f (against S. epidermidis) (Gram-positive bacterial strains), 6e, 6g (against E. coli), 6b, 6e (against K. pneumoniae), and 6d–f (against S. typhimurium) (Gram-negative bacterial strains). Almost all thiosemicarbazones 6a–g had no activity against Gram-positive bacterial strain B. subtilis at these MIC values. Some compounds had strong inhibitory activity against several bacteria, such as 6b (for K. pneumoniae and S. typhimurium), 6d, 6e (for E. coli, K. pneumoniae, and S. typhimurium), 6f (for S. aureus, E. coli, and S. typhimurium), and 6g (for B. subtilis, S. aureus, E. coli, and K. pneumoniae). Some compounds had remarkable inhibitory activity against three clinical MRSA isolates with MIC values of 0.78–6.25 μg/mL. Docking study showed that compound 6g is compatible with the active site of S. aureus DNA gyrase 2XCT, which suggested that the tested compounds inhibited the synthesis of this enzyme.
- 8-cyanobenzothiazinone analogs with potent antitubercular activity
- Abstract: Abstract 8-Nitrobenzothiazinones (BTZs) exemplified by macozinone are a new class of antitubercular agents with exceptionally potent activity. The aryl nitro group has been considered indispensable for activity since this is bioactivated within mycobacteria by the flavoenzyme DprE1 to a reactive nitroso metabolite that covalently labels Cys387. However, the aryl nitro group is a potential liability with regards to safety, stability, and resistance. In this paper, we introduced a nitrile as a bioisosteric replacement of the nitro group, which we hypothesize can maintain a similar covalent mechanism of inhibition, but mitigate against the aforementioned concerns. 8-cyanobenzothiazinone 1d displayed potent antitubercular activity with an MIC of 130 nM and had an improved volume of distribution in mice that increased the intrinsic half-life by twofold compared to macozinone. Analysis of the C-2 substituent of 1d revealed similar structure–activity relationships as observed for macozinone. Overall, the results confirm the 8-nitro group of benzothiazinones can be successfully replaced with a nitrile to retain useful activity and favorable pharmacokinetic properties.
PubDate: 2021-01-13
- Abstract: Abstract 8-Nitrobenzothiazinones (BTZs) exemplified by macozinone are a new class of antitubercular agents with exceptionally potent activity. The aryl nitro group has been considered indispensable for activity since this is bioactivated within mycobacteria by the flavoenzyme DprE1 to a reactive nitroso metabolite that covalently labels Cys387. However, the aryl nitro group is a potential liability with regards to safety, stability, and resistance. In this paper, we introduced a nitrile as a bioisosteric replacement of the nitro group, which we hypothesize can maintain a similar covalent mechanism of inhibition, but mitigate against the aforementioned concerns. 8-cyanobenzothiazinone 1d displayed potent antitubercular activity with an MIC of 130 nM and had an improved volume of distribution in mice that increased the intrinsic half-life by twofold compared to macozinone. Analysis of the C-2 substituent of 1d revealed similar structure–activity relationships as observed for macozinone. Overall, the results confirm the 8-nitro group of benzothiazinones can be successfully replaced with a nitrile to retain useful activity and favorable pharmacokinetic properties.
- Benzopyrylium salts as new anticancer, antibacterial, and antioxidant
agents- Abstract: Abstract Benzopyrylium salts are an unexplored class of compounds and as a first, this study reports them as potential therapeutic agents. In this effort we pursue the synthesis and in vitro anticancer, antibacterial and antioxidant properties of some novel benzopyrylium salts. The benzopyrylium salts were synthesized and further characterized via UV-vis, IR, 1H-NMR, 13C-NMR and mass spectrometry. The benzopyrylium salts were tested in vitro for anticancer activity across NCI 60 cell line panel. PS-CP-4MO showed the best activity against the MDA-MB-435 cell line of melanoma cancer in terms of the least GI50 (1.78 µM), TGI (3.47 µM) and LC50 (6.77 µM) values and showed selectivity against melanoma, colon cancer and leukemia. Mechanistic studies indicate that this compound inhibits MCF-7 cancer cells by inducing apoptosis and abrogates colony formation and wound healing in the cancer cells. Antibacterial studies show that some of the benzopyrylium salts are active on S. aureus (ATCC 29213) and the best active compound PS-CP-5Cl has a MIC of 8 µg/mL. Antioxidant studies indicate that they have good free radical scavenging properties (PS-CP-5Cl showed activity 1.48 times ascorbic acid). Fulfillment of the Lipinski’s parameters of the benzopyrylium salts in silico showed tremendous drug likeness as potential pharmacophore leads.
PubDate: 2021-01-13
- Abstract: Abstract Benzopyrylium salts are an unexplored class of compounds and as a first, this study reports them as potential therapeutic agents. In this effort we pursue the synthesis and in vitro anticancer, antibacterial and antioxidant properties of some novel benzopyrylium salts. The benzopyrylium salts were synthesized and further characterized via UV-vis, IR, 1H-NMR, 13C-NMR and mass spectrometry. The benzopyrylium salts were tested in vitro for anticancer activity across NCI 60 cell line panel. PS-CP-4MO showed the best activity against the MDA-MB-435 cell line of melanoma cancer in terms of the least GI50 (1.78 µM), TGI (3.47 µM) and LC50 (6.77 µM) values and showed selectivity against melanoma, colon cancer and leukemia. Mechanistic studies indicate that this compound inhibits MCF-7 cancer cells by inducing apoptosis and abrogates colony formation and wound healing in the cancer cells. Antibacterial studies show that some of the benzopyrylium salts are active on S. aureus (ATCC 29213) and the best active compound PS-CP-5Cl has a MIC of 8 µg/mL. Antioxidant studies indicate that they have good free radical scavenging properties (PS-CP-5Cl showed activity 1.48 times ascorbic acid). Fulfillment of the Lipinski’s parameters of the benzopyrylium salts in silico showed tremendous drug likeness as potential pharmacophore leads.
- Design, synthesis, docking study and urease inhibitory activity evaluation
of novel 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)- N -arylacetamide
derivatives- Abstract: Abstract In this paper, novel 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-N-arylacetamide derivatives (7a–l) are designed, synthesized, and evaluated in vitro for their urease inhibitor activities. The compounds are synthesized efficiently in three steps in high isolated yields from amines, 2-chloroacetyl chloride, hydrazinecarbothioamide, and carbon disulfide. The molecular docking simulation were performed using AutoDock4 by docking all synthesized compound and standard inhibitors into the crystal structure of Jack bean urease. Comparison between the urease inhibitory activity of compounds 7a–l with the IC50 of (2.85–5.83 µM) and thiourea and hydroxyurea as standards inhibitors with the IC50 of (22.00 and 100.00 µM, respectively) proved the high activity of the synthesized compounds against the mentioned enzyme. Docking results were in good agreement with experimental results and indicate that synthesized compounds could interact well with the active site of the urease enzyme and among all; compound 7j shows more favorable interactions with the active site which confirm its great inhibitory activity with IC50 of 2.85 µM. Therefore, compound 7j might be a promising candidate for further evaluation.
PubDate: 2021-01-12
- Abstract: Abstract In this paper, novel 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-N-arylacetamide derivatives (7a–l) are designed, synthesized, and evaluated in vitro for their urease inhibitor activities. The compounds are synthesized efficiently in three steps in high isolated yields from amines, 2-chloroacetyl chloride, hydrazinecarbothioamide, and carbon disulfide. The molecular docking simulation were performed using AutoDock4 by docking all synthesized compound and standard inhibitors into the crystal structure of Jack bean urease. Comparison between the urease inhibitory activity of compounds 7a–l with the IC50 of (2.85–5.83 µM) and thiourea and hydroxyurea as standards inhibitors with the IC50 of (22.00 and 100.00 µM, respectively) proved the high activity of the synthesized compounds against the mentioned enzyme. Docking results were in good agreement with experimental results and indicate that synthesized compounds could interact well with the active site of the urease enzyme and among all; compound 7j shows more favorable interactions with the active site which confirm its great inhibitory activity with IC50 of 2.85 µM. Therefore, compound 7j might be a promising candidate for further evaluation.
- Development of structure-based pharmacophore to target the β-catenin-TCF
protein–protein interaction- Abstract: Abstract β-catenin concentration is methodically controlled by the Wnt signaling pathway, wherein mutations of this pathway can cause aberrant activation leading to an influx of β-catenin, which is implicated in many cancers, specifically colon cancer. Targeting the β-catenin-TCF interface has become a popular strategy because of its role in the Wnt signaling transduction pathway, but efforts to push a small-molecule inhibitor to clinical success have been futile. In our current study, we attempted to identify druggable “hot spots” at the β-catenin-TCF interface by exploring plausible binding modes of a number of reported and chemically distinct inhibitors and defined their structure-based pharmacophore. Validation of our 4-feature pharmacophore hypothesis was carried out using another series of structure-related inhibitors with reported experimental data. Our hypothesis identified 73% of true actives with high enrichment of the most potent molecules in the test dataset. We speculate that our structure-based pharmacophore query may act as an in silico tool to rapidly screen small-molecule libraries for potentially new scaffolds to disrupt the β-catenin-TCF protein–protein interaction. In addition, our pharmacophore successfully identified actives from a set of structurally similar inhibitors and, ultimately, may be applied as an adjunct tool in the hit-to-lead optimization process.
PubDate: 2021-01-12
- Abstract: Abstract β-catenin concentration is methodically controlled by the Wnt signaling pathway, wherein mutations of this pathway can cause aberrant activation leading to an influx of β-catenin, which is implicated in many cancers, specifically colon cancer. Targeting the β-catenin-TCF interface has become a popular strategy because of its role in the Wnt signaling transduction pathway, but efforts to push a small-molecule inhibitor to clinical success have been futile. In our current study, we attempted to identify druggable “hot spots” at the β-catenin-TCF interface by exploring plausible binding modes of a number of reported and chemically distinct inhibitors and defined their structure-based pharmacophore. Validation of our 4-feature pharmacophore hypothesis was carried out using another series of structure-related inhibitors with reported experimental data. Our hypothesis identified 73% of true actives with high enrichment of the most potent molecules in the test dataset. We speculate that our structure-based pharmacophore query may act as an in silico tool to rapidly screen small-molecule libraries for potentially new scaffolds to disrupt the β-catenin-TCF protein–protein interaction. In addition, our pharmacophore successfully identified actives from a set of structurally similar inhibitors and, ultimately, may be applied as an adjunct tool in the hit-to-lead optimization process.
- Synthesis and evaluation of benzenesulfonic acid derivatives as human
neutrophil elastase (hNE) inhibitors- Abstract: Abstract Herein we report our investigation concerning the development of Human neutrophil elastase (hNE) inhibitors for the treatment of Acute Respiratory Distress Syndrome (ARDS). Various benzenesulfonic acid derived compounds were synthesized and evaluated as competitive inhibitors of hNE. Biological screening revealed that compound 4f shows moderate inhibitory activity (IC50 = 35.2 μM) against hNE. Compound 4f was also superimposed onto the active center of hNE to understand the binding mode.
PubDate: 2021-01-12
- Abstract: Abstract Herein we report our investigation concerning the development of Human neutrophil elastase (hNE) inhibitors for the treatment of Acute Respiratory Distress Syndrome (ARDS). Various benzenesulfonic acid derived compounds were synthesized and evaluated as competitive inhibitors of hNE. Biological screening revealed that compound 4f shows moderate inhibitory activity (IC50 = 35.2 μM) against hNE. Compound 4f was also superimposed onto the active center of hNE to understand the binding mode.
- DDR1 and DDR2: a review on signaling pathway and small molecule inhibitors
as an anticancer agent- Abstract: Abstract Cancer is the 2nd most fatal disease around the globe. Various receptors have been showed to be overexpressed and/or mutated in numerous cancers. Discoidin domain receptors 1 (DDR1) and 2 (DDR2) are one of the novel receptor tyrosine kinases (RTKs), which have been proved to regulate various cellular signaling pathways, cell proliferation, adhesion, migration, matrix remodeling, and dysregulation of these receptors may lead to metastatic cancer progressions. These receptors belong to unique category of RTKs, which require collagen binding for its activation. Yet the mechanism of this extracellular collagen binding and activation of cytosolic kinase domain of the receptors is not clear. Like other RTKs, these receptors also showed its extensive implications in numerous cancers like lung, breast, ovarian, pancreatic cancer and many others. Therefore DDR1 and DDR2 emerge as potential therapeutic targets in preventing cancer. Various small molecule tyrosine kinase inhibitors have been developed against these two receptors and proved to be highly efficacious in reducing tumor progressions. This review would highlight the detailed structure, functions, mechanism of action, signaling pathways of DDR1 and DDR2, their roles in cancer developments and the inhibition of these receptors with numerous inhibitors can be a promising strategy to combat this hefty menace.
PubDate: 2021-01-12
- Abstract: Abstract Cancer is the 2nd most fatal disease around the globe. Various receptors have been showed to be overexpressed and/or mutated in numerous cancers. Discoidin domain receptors 1 (DDR1) and 2 (DDR2) are one of the novel receptor tyrosine kinases (RTKs), which have been proved to regulate various cellular signaling pathways, cell proliferation, adhesion, migration, matrix remodeling, and dysregulation of these receptors may lead to metastatic cancer progressions. These receptors belong to unique category of RTKs, which require collagen binding for its activation. Yet the mechanism of this extracellular collagen binding and activation of cytosolic kinase domain of the receptors is not clear. Like other RTKs, these receptors also showed its extensive implications in numerous cancers like lung, breast, ovarian, pancreatic cancer and many others. Therefore DDR1 and DDR2 emerge as potential therapeutic targets in preventing cancer. Various small molecule tyrosine kinase inhibitors have been developed against these two receptors and proved to be highly efficacious in reducing tumor progressions. This review would highlight the detailed structure, functions, mechanism of action, signaling pathways of DDR1 and DDR2, their roles in cancer developments and the inhibition of these receptors with numerous inhibitors can be a promising strategy to combat this hefty menace.
- Synthesis of 4-oxotetrahydropyrimidine-1(2H)-carboxamides derivatives as
capsid assembly modulators of hepatitis B virus- Abstract: Abstract We report herein the synthesis and evaluation of phenyl ureas derived from 4-oxotetrahydropyrimidine as novel capsid assembly modulators of hepatitis B virus (HBV). Among the derivatives, compound 27 (58031) and several analogs showed an activity of submicromolar EC50 against HBV and low cytotoxicities (>50 μM). Structure–activity relationship studies revealed a tolerance for an additional group at position 5 of 4-oxotetrahydropyrimidine. The mechanism study indicates that compound 27 (58031) is a type II core protein allosteric modulator (CpAMs), which induces core protein dimers to assemble empty capsids with fast electrophoresis mobility in native agarose gel. These compounds may thus serve as leads for future developments of novel antivirals against HBV.
PubDate: 2021-01-11
- Abstract: Abstract We report herein the synthesis and evaluation of phenyl ureas derived from 4-oxotetrahydropyrimidine as novel capsid assembly modulators of hepatitis B virus (HBV). Among the derivatives, compound 27 (58031) and several analogs showed an activity of submicromolar EC50 against HBV and low cytotoxicities (>50 μM). Structure–activity relationship studies revealed a tolerance for an additional group at position 5 of 4-oxotetrahydropyrimidine. The mechanism study indicates that compound 27 (58031) is a type II core protein allosteric modulator (CpAMs), which induces core protein dimers to assemble empty capsids with fast electrophoresis mobility in native agarose gel. These compounds may thus serve as leads for future developments of novel antivirals against HBV.
- Synthesis of macrocyclic α -ketoamide as a selective and reversible
immunoproteasome inhibitor- Abstract: Abstract In recent years, the human immunoproteasome has emerged as an attractive therapeutic target for various diseases, leading to a growing interest in the discovery of immunoproteasome inhibitors that selectively target specific subunits. Herein we report the design, synthesis, and evaluation of a new immunoproteasome inhibitor that feature a macrocyclic ring containing an internal α-ketoamide warhead. This compound is a selective and reversible inhibitor of immunoproteasome subunits β1i and β5i and shows essentially no inhibition of constitutive proteasome subunits.
PubDate: 2021-01-11
- Abstract: Abstract In recent years, the human immunoproteasome has emerged as an attractive therapeutic target for various diseases, leading to a growing interest in the discovery of immunoproteasome inhibitors that selectively target specific subunits. Herein we report the design, synthesis, and evaluation of a new immunoproteasome inhibitor that feature a macrocyclic ring containing an internal α-ketoamide warhead. This compound is a selective and reversible inhibitor of immunoproteasome subunits β1i and β5i and shows essentially no inhibition of constitutive proteasome subunits.
