- Synthesis of Ofornine mimics from natural product l-vasicine as anti-hypertensive agents
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We report the chemical synthesis of Ofornine mimics from l-vasicine, structure-activity relationship studies and their in vivo screening for anti-hypertensive action in Wistar rats. It was observed that most of the analogs possessed anti-hypertensive effect; however, the duration of the effect was variable and mostly transient. The results demonstrated that the analogs 12, 13, 14, 15, and 16 showed a sharp and significant decrease in systolic and diastolic blood pressure for 30–60 min after intravenous administration. Analog (S)-(3-hydroxypyrrolidin-1-yl)(2-(pyridin-4-ylamino)phenyl)methanone (8) showed a significant decrease in blood pressure in a dose dependent manner whose maximal response lowered to 79.29 ± 4.26 mmHg of SBP and 62.55 ± 2.9 of DBP at 10 mg/kg intravenous dose. Further, the significant anti-hypertensive effect of 8 lasted for about 2.5 h at 10 mg/kg dose. We also evaluated the acute toxicity of the analog 8 as per the OECD guidelines and the compound was found to be safe up to the dose of 2000 mg/kg body weight. These preclinical findings suggest that the analog 8 could be considered as a promising lead and a durable anti-hypertensive drug candidate and deserves further investigation. The SAR studies clearly showed that the amide, hydroxyl and pyridine ring plays important role in showing the activity.
- Aga, Mushtaq A.,Rayees, Sheikh,Rouf, Abdul,Kumar, Brijesh,Sharma, Anjna,Nagaraju,Singh, Gurdarshan,Taneja, Subhash C.
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- Exploring Derivatives of Quinazoline Alkaloid l-Vasicine as Cap Groups in the Design and Biological Mechanistic Evaluation of Novel Antitumor Histone Deacetylase Inhibitors
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l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency.
- Ahmad, Mudassier,Aga, Mushtaq A.,Bhat, Javeed Ahmad,Kumar, Brijesh,Rouf, Abdul,Capalash, Neena,Mintoo, Mubashir Javeed,Kumar, Ashok,Mahajan, Priya,Mondhe, Dilip Manikrao,Nargotra, Amit,Sharma, Parduman Raj,Zargar, Mohmmad Afzal,Vishwakarma, Ram A.,Shah, Bhahwal Ali,Taneja, Subhash Chandra,Hamid, Abid
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p. 3484 - 3497
(2017/05/05)
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- Natural (-)-vasicine as a novel source of optically pure 1-benzylpyrrolidin-3-ol
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A facile and scalable methodology for the preparation of optically active (3S)-1-benzylpyrrolidin-3-ol (3), an important drug precursor, is reported. Starting from the naturally occurring alkaloid (-)-vasicine (1), a major alkaloid of the plant Adhatoda vasica, 3 was obtained in 84% overall yield (Scheme 3). Copyright
- Aga, Mushtaq A.,Kumar, Brijesh,Rouf, Abdul,Shah, Bhahwal A.,Andotra, Samar S.,Taneja, Subhash C.
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p. 969 - 977
(2013/06/27)
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- PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE N-BENZYL-3 HYDROXYPYRROLIDINES
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The present invention relates to a facile, highly efficient and economical process for the preparation of optically active N-benzyl-3-hydroxypyrrolidine in high yield from a naturally occurring alkaloid vasicine. The natural alkaloid vasicine is used as a precursor of (S)—N-benzyl-3-hydroxypyrrolidine and (R)—N-benzyl-3-hydroxypyrrolidines which can easily be sourced from the medicinal plant Adatoda vasica by the method known in the art and transformed to optical isomers (R) and (S)—N-benzyl-3-hydroxypyrrolidine by the method described in the present invention.
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Page/Page column 4
(2012/05/04)
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- A PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE N-BENZYL-3 HYDROXYPYRROLIDINES
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The present invention relates to a facile, highly efficient and economical process for the preparation of optically active N-benzyl-3-hydroxypyrrolidine in high yield from a naturally occurring alkaloid vasicine. The natural alkaloid vasicine is used as a precursor of (S)-N-benzyl-3-hydroxypyrrolidine and (R)-N-benzyl-3-hydroxypyrrolidines which can easily be sourced from the medicinal plant Adatoda vasica by the method known in the art and transformed to optical isomers (R) and (S)-N-benzyl-3-hydroxypyrrolidine by the method described in the present invention.
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Page/Page column 11
(2010/07/10)
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