Rational Design and Synthesis of Isatin-Chalcone Hybrids Integrated with 1H-1,2,3-Triazole: Anti-Proliferative Profiling and Molecular Docking Insights.

In this study, a series of isatin-chalcone linked triazoles were synthesized using Cu-promoted Azide-Alkyne Cycloaddition (CuAAC) reaction and evaluated for their cytotoxicity against various cancer cell lines. The most potent compound displayed approximately 2.5 times greater activity compared to both reference compounds against ovarian cancer cell lines. These findings were supported by caspase-mediated apoptosis and molecular docking analyses. Docking revealed comparable VEGFR-2 affinities for 5 b and 5-FU but highlighted stronger interaction of 5 b with EGFR, evident from its lower docking score. Overall, these results signify the notable anti-proliferative potential of most synthesized hybrids, notably emphasizing the efficacy of compound 5 b in suppressing cancer cell growth.

Recent developments in biological aspects of chalcones: the odyssey continues.

INTRODUCTION: Chalcones are attractive to synthetic chemists because they are easy to prepare, have a large number of replaceable hydrogens, thereby having significant biological potential. Chalcones and their derivatives (carbocyclic as well as heterocyclic) exhibit a range of biological properties including anticancer, antimalarial, antioxidant, anti-inflammatory and anti-tubercular activities. Their promising biological profile, along with their ease of synthetic manipulations, have triggered the design and development of new chalcone derivatives as well as their conjugates with active pharmacophores affording therapeutic templates targeting various diseases. Areas covered: This review focuses on synthesized substituted chalcones as well as chalcone-based molecular conjugates that have been developed between 2015 and 2018. Furthermore, their structure-activity relationships with an emphasis on their mechanism of action and docking studies along with their future therapeutic applications. Expert opinion: A recent upsurge in scientific literature encompassing the synthesis of new chalcone-derivatives as well as its role in ameliorating the activity profiles via amalgamation with other pharmacophores has clearly established the importance of chalcones in present-day drug discovery. As a point, we, the authors, believe that new effective scaffolds can be developed from chalcones with an added advantage of being available at a low cost.

Traditionally used wild edible plants of district Udhampur, J&K, India.

BACKGROUND: Wild edible plants (WEPs) refer to edible species that are not cultivated or domesticated. WEPs have an important role to play in poverty eradication, security of food availability, diversification of agriculture, generation of income resources, and alleviating malnutrition. In the present study, an inventory of traditionally used WEPs from Udhampur district of J&K, India, has been prepared. METHODS: A systematic and extensive ethnobotanical survey was carried out in different villages of the district for the collection of information on WEPs. The data collected through questionnaire and interviews was then analyzed for cultural importance index (CI) and factor informant consensus (Fic) to know the cultural significance of WEPs and consensus for the knowledge of WEPs among the informants. RESULTS: A total of 90 plant species belonging to 45 families and 78 genera were edible and serve as wild phytofoods in the present study. Species richness of wild edible species was the maximum for vegetables (46 species) followed by fruits (37 species) and medicinal plants (36 species). Culturally (on the basis of CI), the most important vegetable and fruit species were Diplazium esculentum, Fumaria indica, Taraxacum campylodes, Urtica dioica, Phyllanthus emblica, Punica granatum, Cordia dichotoma, Syzygium cumini, Ficus palmata, etc. The highest use-report (626) was recorded for vegetables whereas the maximum mean use-report (14.8) was recorded for fruits. On an average, 20.7 wild edible species were used per informant. Informant consensus index (Fic) varied between 0.83 and 0.94 for raw vegetables and preserved vegetables, respectively. CONCLUSION: One of the most important issues of this era is hunger for which one of the possible solutions is the usage of WEPs. The local populace of Udhampur has good knowledge of WEPs, and this legacy of traditional culture must be conserved.

Recent insights into synthetic ß-carbolines with anti-cancer activities.

Cancer, an uncontrolled and rapid proliferation of abnormal cells, has become one of the leading cause of death worldwide. The development of resistance among the numerous drugs in clinical use has provided strong impetus for the identification and development of novel cancer therapeutics. ß-carbolines constitute an important class of pharmacologically active scaffolds known to exert their anticancer activities via diverse mechanisms. The purpose of present review article is to update the readers on the current developments in ß-carbolines with an emphasis on synthetic strategies, structure-activity relationships, mechanism of action and in vivo studies wherever possible.

1H-1,2,3-triazole-tethered uracil-ferrocene and uracil-ferrocenylchalcone conjugates: Synthesis and antitubercular evaluation.

Copper-catalyzed azide-alkyne [3 + 2] cycloaddition has been utilized for preparing a series of 1H-1,2,3-triazoles with the purpose of probing structure-activity relationships among a uracil-ferrocene-triazole conjugate family. The antitubercular evaluation studies revealed an improvement in activity with the introduction of a ferrocene nucleus among N-alkylazido-uracil precursors, with a preference for a bromo-substituent along with moderate chain lengths of n = 2-6. The reported protocol is a successful approach for integrating uracil-ferrocene-chalcone functionalities tethered via 1H-1,2,3-triazole rings with apparent physicochemical stability.

Synthesis and antiprotozoal activity of mono- and bis-uracil isatin conjugates against the human pathogen Trichomonas vaginalis.

A library of mono- and bis-uracil isatin conjugates were synthesized and subjected for the assessment of their in vitro activity against the protozoal pathogen Trichomonas vaginalis. The structure activity studies (SAR) revealed that the bis-uracil-isatin based conjugates were more effective than their corresponding mono conjugates in inhibiting the growth of T. vaginalis at approximately 10 µM with no visual effect on mammalian cells at the same concentration.

Ethnomedicinal plants of Shankaracharya Hill, Srinagar, J&K, India.

ETHNOPHARMACOLOGICAL RELEVANCE: Primitive human societies have always relied on plants and plant products for various remedies. In certain areas, these folk medical prescriptions are endemic and have survived through ages from one generation to the next through word of mouth. They do not exist as written knowledge. The present study was undertaken with an objective of documenting the ethnobotanical information of medicinal plants of Shankaracharya Hill by taking the help of local herbalists, elderly and knowledgeable people. MATERIAL AND METHODS: The data was quantitatively analysed using use-value (UV), informant consensus factor (ICF) and fidelity level (Fl%) indices. RESULTS: Total 130 plant species from 57 families and 111 genera were ethno-medicinally utilized by the 103 informants interviewed in the present study. The most used families were Asteraceae, Rosaceae, Lamiaceae, Fabaceae and Brassicaceae. The medicinal plants were mainly herbs (79.2%). Leaves were the most used (27.6%) plant part followed by whole plant (14.8%), root (11.4%) and seed (10.5%). The most important species on the basis of UV were Viola odorata, Taraxacum campylodes, Aesculus hippocastanum, Artemisia absinthium, Daucus carota, Thymus serphyllum, Ephedra gerardiana and Salvia moorcroftiana. The values ICF ranged between 0.93 and 0.76. Only Epilobium hirsutum recorded 100% Fl. Some of the most important medicinal plants with high Fl values were Tribulus terrestris, Asparagus officinalis, Trifolium repens, Anemone biflora, Melia azedarach, A. absinthium, Lonicera quinquelocularis, Rosa webbiana, D. carota, Oxalis corniculata and Potentilla reptans. CONCLUSION: The contribution of plant parts collected through destructive methods was 29.5%. Harvesting of roots, rhizomes, bulbs and corm kills the parent plant and could be a severe threat for survival of the often rare and slowly reproducing medicinal plants, and therefore need sustainable utilization and conservation strategies. Ethnomedicinal species like A. absinthium, A. hippocastanum, D. carota, M. azedarach, T. campylodes, T. serphyllum, T. terrestris having high number of citations, UV and FL should be analyzed for phytochemicals and pharmacology.

Traditional phytoremedies for the treatment of menstrual disorders in district Udhampur, J&K, India.

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal remedies form an integral part of healing and are considered to be the oldest forms of health care known to mankind. The present study aims to document traditional phytoremedies for the treatment of menstrual disorders in Udhampur district of J&K, India. MATERIAL AND METHODS: The informants were interviewed directly and information was gathered about plants used in different menstrual disorders. The data was further analyzed for use-value (UV), factor informant consensus (Fic) and fidelity level (Fl). RESULTS: In all, 62 informants were interviewed. Most of the informants (66%) were females. The patients prefer female healers over male vaids and hakims. A total of 50 plants were used to cure different menstrual disorders. Seeds were found to be of utmost medicinal importance (43.8%) followed by leaves (20.8%) and fruits (16.7%). Oral administration was observed to be the main mode (90.0%) of intake of medicine. The plants with high use-value were Triticum aestivum (UV=1.76), Taraxacum officinale (UV=1.16), Citrus limon (UV=0.95), Allium cepa (UV=0.79), Cicer arietinum (UV=0.77), Trigonella foenum-graecum (UV=0.66), Rubia manjith (UV=0.56), Ocimum tenuiflorum (UV=0.56) and Oryza sativa (UV=0.52). The various menstrual disorders were classified into 7 categories. The values of Fic varied between 0.96 (dysmenorrhea, itching and foul smell) and 0.92 (menorrhagia). The 100% Fl value was scored by 20 plants. Leucorrhea reported the highest 5 plants with 100% Fl. Nearly 40% of the formulations had two or more plants. CONCLUSION: Plants used for the treatment of different menstrual disorders were documented and analyzed for ethnogynecological problems. The study revealed some plants like Triticum aestivum, Rubia manjith, Dalbergia sissoo, Raphanus sativus, Citrus limon, Allium cepa, Trigonella foenum-graecum, Elettaria cardamomum etc. to be of great importance vis a vis menstrual disorders. Further pharmacological studies of these plants may provide some important drugs for the treatment of common menstrual disorders.

1H-1,2,3-triazole tethered isatin-ferrocene conjugates: Synthesis and in vitro antimalarial evaluation.

1H-1,2,3-triazole tethered isatin-ferrocene conjugates were synthesized and evaluated for their antiplasmodial activities against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. The conjugates 5f and 5h with an optimum combination of electron-withdrawing halogen substituent at C-5 position of isatin ring and a propyl chain, introduced as linker, proved to be most potent and non-cytotoxic among the series with IC50 values of 3.76 and 4.58 µM against 3D7 and W2 strains, respectively.

Highly potent anti-proliferative effects of a gallium(III) complex with 7-chloroquinoline thiosemicarbazone as a ligand: synthesis, cytotoxic and antimalarial evaluation.

A gallium(III) complex with 7-chloroquinoline thiosemicarbazone was synthesized and characterized. The complex proved to be thirty-one times more potent on colon cancer cell line, HCT-116, with considerably less cytotoxicity on non-cancerous colon fibroblast, CCD-18Co, when compared to etoposide. Its anti-malarial potential on 3D7 isolate of Plasmodium falciparum was better than lumefantrine.

1H-1,2,3-triazole tethered mono- and bis-ferrocenylchalcone-ß-lactam conjugates: synthesis and antimalarial evaluation.

A series of ferrocenylchalcone-ß-lactam conjugates were synthesized and evaluated against 3D7 (CQ-Sensitive) and W2 (CQ-Resistant) strains of Plasmodium falciparum. The SAR studies revealed the dependence of activities at N-1 substituent of ß-lactam ring with compounds being more potent on resistant strain. The compound 9f and 9l with N-cyclohexyl substituent proved to be the most potent and non-cytotoxic among the series exhibiting IC50 values of 2.36 and 2.43 µM respectively, against W2 strain of P. falciparum.

N-Propargylated isatin-Mannich mono- and bis-adducts: synthesis and preliminary analysis of in vitro activity against Tritrichomonas foetus.

Cu(I)Cl promoted synthesis of N-propargylated-isatin Mannich mono- and bis-adducts with an extension towards the synthesis of N-propargylated-isatin-7-chloroquinoline conjugates was described. The synthesized scaffolds were evaluated for their in vitro activity against the veterinary protozoal pathogen Tritrichomonas foetus and cytotoxicity against human prostate (PC-3) cancer cell line. The preliminary evaluation data revealed the enhancement in the activity profiles with the introduction of 7-chloroquinoline ring with the most active conjugates 7a, 7c and 7d exhibiting an IC50 of 22.2, 11.3 and 24.5 µM respectively against T. foetus and minimal toxicity against human prostate (PC-3) cell lines.

Traditional knowledge on poisonous plants of Udhampur district of Jammu and Kashmir, India.

ETHNOPHARMACOLOGICAL RELEVANCE: Poisonous plants comprise the third largest category of poisons known around the world. Other than affecting the humans directly, they are the major cause of economic losses in the livestock industry since the advent of civilisation. Aim of the present study was to collect and systematically document the traditional knowledge of poisonous plants of Udhampur District for the benefit of humanity before it is entombed forever. MATERIAL AND METHODS: Direct interviews of the informants were conducted and the plants identified as poisonous by them were collected, identified and herbarium sheets were prepared. The data collected through interviews was analysed with two quantitative tools viz. the factor informant consensus and fidelity level. RESULTS: A total of 90 toxic plants were listed from the study site. Most dominant toxic families were Fabaceae, Asteraceae, Solanaceae, Apocynaceae and Euphorbiaceae. Most of the poisonous plants were herbs (57.1%) and the whole plant toxicity was reported to be the highest (32.4%) followed by leaves (23.1%). According to the factor informant consensus, gastrointestinal category had the greatest agreement closely followed by the death category. The most important species on the basis of fidelity level for gastrointestinal category were Cannabis sativa, Cassia occidentalis, Cuscuta reflexa, Euphorbia helioscopia and Euphorbia hirta, for death category were Anagalis arvensis, Embelia robusta and Prunus persica, for dermatological category Euphorbia royleana, Leucaena leucocephala, Parthenium hysterophorus and Urtica dioica, and for sexual illness category were Calotropis procera and Carica papaya. CONCLUSION: Further phytochemical and pharmacological studies are required to ascertain the toxic components of the poisonous plants, so that they may be utilised for the betterment of future generations.

Ethnomedicinal plants used by the villagers of district Udhampur, J&K, India.

UNLABELLED: Plants are an integral part of life in many indigenous communities. Besides, being the source of food, fodder, fuel, etc., the use of plants as herbal medicines in curing several ailments goes parallel to the human civilization. Ethnopharmacology involves the investigation of the plants used by the traditional communities and further understand the pharmacological basis of these culturally important medicinal plants. Present study was conducted to enlist the medicinal plants used by the local inhabitants of Udhampur district of Jammu and Kashmir, India. MATERIAL AND METHODS: Direct interviews of the 182 informants were conducted. The data generated through interviews was analysed using quantitative tools like use-value, factor informant consensus and fidelity level. RESULTS: A total of 166 species of flowering plants belonging to 63 families and 145 genera were observed to be medicinal and used to cure 78 ailments. Medicinal plants were mainly from Asteraceae, Solanaceae, Lamiaceae, Poaceae, Fabaceae and Amaranthaceae families. Leaves were the most used plant part in the medicinal preparations. The most important medicinal species of the present study site as per the use-value (UV) were: Achyranthes aspera, Zanthoxylum armatum, Acorus calamus, Syzygium cumini, Phyllanthus emblica, Plumbago zeylanica etc. The important ailment categories classified on the basis of factor informant consensus (Fic) were diabetes, external parasite, liver complaints and gastrointestinal disorders. The maximum number of species was utilized to cure gastrointestinal and dermatological ailments. Important species for each ailment category were also assessed using fidelity level. It was found that the older informants provided more information about the ethnomedicinal plants, but this valuable treasure of traditional knowledge is depleting significantly with the decrease in age and increase in educational level. CONCLUSION: The results of present ethnobotanical survey reveal the rich wealth of indigenous knowledge associated with the villagers of Udhampur district. A number of plants with a high citation values have given some leads for the further pharmocological research. Apart from these highly cited plants, studies need to be done on some other promising plants like Anagallis arvensis, Euphorbia hirta, Ficus benghalensis, Fumaria indica, Prunus persica, Rubus ellipticus, Taraxacum officinale, Tribulus terrestris etc.

Azide-alkyne cycloaddition en route towards 1H-1,2,3-triazole-tethered ß-lactam-ferrocene and ß-lactam-ferrocenylchalcone conjugates: synthesis and in vitro anti-tubercular evaluation.

A diverse range of triazoles were prepared following well established, Cu-mediated azide-alkyne cycloaddition reactions with the aim of probing the anti-tubercular structure-activity relationships (SAR) within the ß-lactam-ferrocene-triazole conjugate family. The anti-tubercular evaluation studies of the synthesized conjugates revealed that none of the scaffolds exhibited any activity that restricted mycobacterial growth even at high doses. The introduction of various substituents onto the N-1 of the ß-lactam ring, introducing mono- or di-ferrocenylchalcone substituents at the C-3 position as well as introducing a spacer of varying chain length failed to produce any significant enhancement in the activity profiles. The described protocol was a successful attempt on the inclusion of a ferrocene nucleus in the ß-lactam family tethered via triazole linkers having metabolic stability and physicochemical favourability.

Synthesis of novel 1H-1,2,3-triazole tethered C-5 substituted uracil-isatin conjugates and their cytotoxic evaluation.

The present manuscript describes the synthesis of uracil-isatin hybrids via azide-alkyne cycloadditions and their cytotoxic evaluation against three human cancer cell lines viz. HeLa (cervix), MCF-7 (breast) and DU145 (prostate) using MTT assay. The evaluation studies revealed the dependence of cytotoxicity on C-5 substituents of both uracil and isatin as well as the alkyl chain length with compounds 6g and 6k showing IC(50) values 18.21 and 13.90 µM respectively against DU145 cell lines. Most of the synthesized conjugates exhibited considerable selectivity against MCF-7 and DU145 cell lines.

Synthesis and in vitro anti-tubercular evaluation of 1,2,3-triazole tethered ß-lactam-ferrocene and ß-lactam-ferrocenylchalcone chimeric scaffolds.

Twenty different triazoles were prepared to probe the anti-tubercular structure-activity relationships (SAR) within the ß-lactam-ferrocene-triazole conjugate family. The compounds have been synthesized by copper-catalyzed "click chemistry". In vitro anti-tubercular activity was determined for each compound but the synthesized hybrids failed to inhibit Mycobacterium tuberculosis growth even at high doses. The manuscript assumes significance as this is the first report on the inclusion of ferrocene nucleus in the well established ß-lactam family via triazole linkers with reputed physicochemical profiles.

Synthesis, docking and in vitro antimalarial evaluation of bifunctional hybrids derived from ß-lactams and 7-chloroquinoline using click chemistry.

1,2,3-Triazole tethered ß-lactam and 7-chloroquinoline bifunctional hybrids were synthesized and evaluated as potential antimalarial agents. Activity against cultured Plasmodium falciparum was dependent on the N-substituent of the ß-lactam ring as well as the presence of bis-triazole at the C-3 position. The observed activity profiles were further substantiated by docking studies via inhibition of P. falciparum dihydrofolate reductase (PfDHFR), a potential target for the development of new anti-malarials.