Synthesis, molecular docking, and biological evaluation of novel 1,2,4-triazole-isatin derivatives as potential Mycobacterium tuberculosis shikimate kinase inhibitors.

The issue of emerging resistance to antitubercular drugs has created a formidable barrier in the effective prevention and cure of tuberculosis globally. In an effort to search for new antimycobacterial agents, possibly comprising new pharmacophore, novel triazole-isatin derivatives were designed as Mycobacterium tuberculosis shikimate kinase inhibitors and synthesized by microwave-assisted method. The synthesized molecules were evaluated for their antimycobacterial activity by MABA assay against M. tuberculosis H37Rv. The molecule 5h demonstrated MIC of 0.8 µg/ml and good safety profile with higher selectivity index with HEK293 cell line. The antimycobacterial activity was further substantiated with molecular docking studies. The triazole-isatin derivatives showed significant binding interactions with amino acid residues in the active site of the enzyme. These studies revealed that molecule 5h could act as a potential lead molecule for further studies to find new target-directed molecules.

Evaluation of Biological Activity of Derivatives of 1,3,4-Thiadiazole, 1,3,4-Oxadiazole and 1,2,4-Triazole.

OBJECTIVE: 1,3,4-thiadiazole (A), 1,3,4-oxadiazole (B) and 1,2,4-triazole (C) derivatives have been known for their immense pharmacotherapeutic potential. The current research article attempts to further explore and understand the probable biochemical mechanism related to antiinflammatory activity of derivatives. METHODS: The screened A, B and C derivatives were investigated for both in-vitro (Erythrocyte Membrane stabilization activity, Proteinase enzyme inhibitory activities) and in-vivo correlation using acute and chronic anti-inflammatory potential by carrageenan induced rats paw edema and cotton pellet granuloma methods, respectively. The activity was studied after interpreting acute toxicity studies results. RESULTS: In vitro studies in the case of Erythrocyte Membrane stability and Proteinase enzyme inhibitory activities exhibited by A, B, and C at 100 ppm were found to be 48.89%, 51.08% and 50.08% and 66.78%, 76.91% and 57.41%, respectively. The maximum toxic dose was found to be 2000 mg/kg. The derivatives were studied for two-dose levels viz; Lower (100 mg/kg) and higher dose (200 mg/kg). In rat paw edema, maximum decrease was obtained for A (50.05%), B (50.05%) and C (51.06%) at lower and higher dose at 68.76%, 55.61%, and 65.26%, respectively for effect up to 24 h. In the chronic model of cotton pellet granuloma viz; higher and lower doses of A, B and C exhibited 38.15%, 33.19% and 30.25 % and 19.45%, 18.55% and 17.55 %, respectively. CONCLUSION: The studied models depicted that derivatives A, B and C have the probable potential as anti-inflammatory agents. Further studies need to be undertaken to explore their potential in the different therapeutic areas.

Ornithine Decarboxylase Inhibition: A Strategy to Combat Various Diseases.

Ornithine decarboxylase is the first enzyme in the polyamine biosynthetic pathway. It is the rate-limiting enzyme which is included during the change of ornithine to putrescine which is the first polyamine. Polyamines (putrescine, spermidine, spermine) are natural and synthetic compounds which contain two or more amino group. Polyamines are highly implicated in cellular functions such as cell growth & multiplication, DNA stabilization, gene transcription and translation, ion-channel activity, etc. Elevated levels of polyamines are found in highly proliferating tumor cells. Hence inhibition of this enzyme was found useful in cancer. α-DL-difluoromethylornithine(DFMO) (Eflornithine) an enzyme- activated irreversible inhibitor was the first of this type. However, its use as an anticancer agent did not continue for long due to various reasons. Polyamines have also been found to play an important role in other infectious microorganisms. Eflornithine is successfully used in diseases such as African sleeping sickness and is being researched against a number of tropical diseases. It is widely used against hirsutism in women. Various other product (putrescine) based analogs and transition state or PLP (cofactor) based analogs are being synthesized against diseases such as Leishmaniasis, Malaria and others discussed in the article.

Elucidation of Flavonoids from Carissa congesta, Polyalthia longifolia, and Benincasa hispida Plant Extracts by Hyphenated Technique of Liquid Chromatography-mass Spectroscopy.

BACKGROUND: Carissa congesta (CC), Polyalthia longifolia (PL), and Benincasa hispida (BH) are economically important plants. OBJECTIVE: Current research encompasses identification of quercetin and rutin and their analogues by liquid chromatography-mass spectroscopy (LC-MS) from the selected plant species. MATERIALS AND METHODS: Fresh roots, leaves, and seeds of CC, PL, and BH plants respectively were shade-dried followed by extraction and elucidation of rutin and quercetin by LC-MS. RESULTS: Structural elucidation of CC, PL, and BH extracts revealed the presence of flavonoids such as quercetin (m/z 301) and rutin (m/z 610) as the parent ions along with presence of close analogues such as quercetin-O-hexoside, Vicenin 2, quercetin-3-O-xyloside/arabinoside, and quercetin-3-O-glucoside were identified as fragments. CONCLUSIONS: Thus, CC, PL, and BH extracts revealed the presence of flavonoids belonging to the class of flavonols such as rutin and quercetin. SUMMARY: Quercetin and rutin were identified from CC roots, PL leaves and BH seeds by liquid chromatography-mass spectroscopy.Quercetin was characterized at (m/z 301) and rutin (m/z 610) as the parent ion peaks.Analogues such as quercetin-O-hexoside, Vicenin 2 and quercetin-3-O-glucoside were identified as fragments.

Structural elucidation of chemical constituents from Benincasa hispida seeds and Carissa congesta roots by gas chromatography: Mass spectroscopy.

BACKGROUND: Benincasa hispida (BH) and Carissa congesta (CC) are regarded as ethnopharmacological imperative plants in Asian countries. OBJECTIVE: Phytochemical screening of the extracts has shown the presence of steroids, flavonoids, saponins, glycosides, tannins, phenolic compounds, fixed oils, and fats in the BH and CC extracts. The presence of lupeol has been reported previously by us using high-performance thin-layer chromatography and high-performance liquid chromatography. MATERIALS AND METHODS: Present research studies encompasses identification of chemical constituents in BH seeds and CC roots petroleum ether extracts by hyphenated technique such as gas chromatography-mass spectroscopy (MS) which when coupled gives a clear insight of constituents. RESULTS: The components were identified by matching mass spectra with MS libraries. There were 13 and 10 different compounds analyzed from CC and BH, respectively. The components present were Pentanoic acid, 5-hydroxy, 2,4-butylphenyl; n-Hexadecanoic acid (Palmitic acid); Sulfurous acid, 2-ethylhexylhepatdecyl ester; n-Tridecane; 6-methyltridecane; (9E, 12E)-9,12-Octadecadienyl chloride, Hexadecanoic acid, 3-(trimethylsilyl)-oxy] propyl ester; 9,12-Octadecadenoic acid, 2 hydroxy-1-(hyroxymethylethyl) ester; 9,12-Octadecadienoic acid, 2,3 dihydroxypropyl ester; n-Propyl-9,12-Octadecadienoate, Lupeol; Taraxasterol; 6a, 14a-Methanopicene, perhydro-12,4a, 61a, 9,9,12a-hepatmethyl-10-hydoxy and 9-Octadecene; 2-Isoprpenyl-5-methyl-6-hepten-1-ol; n-Hexadecanoic acid, 2-hyroxy-1-(hydroxymethyl) ethyl ether; Butyl-9,12-Octadecadieonate; Friedoolean-8-en-3-one; friedours-7-en-3-one; 13,27-Cyclosuran-3-one; Stigmaste-7,25-dien-3-ol (3ß, 5α); Stigmasta-7,16-dien-3-ol; chrondrillasterol in BH seeds and CC roots extracts respectively. CONCLUSION: Eluted components from the extracts could provide further researchers to work with various pharmacological activities related models and studies.

Farnesyltransferase inhibitor as anticancer agent.

Ras protein plays pivotal roles in control of normal and transformed cell growth. These ras genes are mutated in 30% of human cancer. For functioning of Ras protein its prenylation (farnesylation) is required. Therefore targeting Ras farnesylation is valuable approach for cancer treatment. Farnesyltransferase inhibitor (FTI) has been developed as anticancer drug and is currently evaluated in clinical trials. Different types of FTI have been identified that inhibit Ras farnesylation. FTI in combination with some cytotoxic antineoplastic drugs, exhibit additive effects.