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A series of novel 4-(2-isonicotinoylhydrazono) butanoic acid derivatives (3a-n) were designed, synthesized and evaluated for anti-tubercular activity. The synthesized compounds were characterized by 1H-NMR, 13C-NMR, FT-IR, and Mass Spectroscopic analyses. The synthesized compounds were evaluated for anti-mycobacterial activity against avirulent (H37Ra), virulent (H37Rv) as well as INH-Resistant strains that showed good to moderate activity. The MIC and MBC values observed were found identical for both H37Ra and H37Rv. 3a, 3c, 3e and 3i were found as the most potent in the series with a MIC and MBC = 1µg/ml. The compounds showed moderate activity against the INH-resistant clinical isolates as well. The potent compounds 3a, 3c and 3i showed least cytotoxicity towards normal human cell lines (HEK-293, AML12 and RAW-264). Molecular docking studies of the synthesized compounds performed with the protein target M. tuberculosis InhA in complex with NADH (PDB ID: 4DRE) revealed that compound 3c showed the best dock score of -7.798. The compound 3c forms two hydrogen bonds with Valine (VAL 65) and Serine (SER 20) whereas INH forms two hydrogen bonds with Valine (VAL 65) and Glycine (GLY 96). Both the benzene ring and pyridine ring of the compound 3c displayed the π-π interactions with Phenylalanine (PHE 41). Physicochemical properties and pharmacokinetic profiling assessed for the synthesized compounds were found to follow Lipinski’s rule using Swiss ADME online prediction tools. These findings make them promising candidates for the future development of new anti-tubercular agents.

Nigella sativa is an annual herb identified as having curative and remedial properties for treating the certain health conditions namely, asthma, nasal congestion, bronchitis, and metabolic disorders due to its immune boosting and antioxidant benefits. Studies have shown that the chemical constituents of N. sativa, especially thymoquinone, have renoprotective effects against nephrotoxic agents induced kidney complications. Many drugs that are used in the treatment of cancer are known to induce nephrotoxicity. Many studies have been analyzed and reported in which the various chemotherapeutic agents such as doxorubicin, cisplatin, gentamicin, and methotrexate are used to induce nephrotoxicity. Thymoquinone has certain protective properties such as antioxidant activity, antiinflammatory and antiapoptotic properties that renders it as a potential therapeutic target for the treatment of induced renal diseases. In this chapter, the protective roles of N. sativa against the induced renal disorders such as nephrotoxicity, renal ischemia, and diabetic nephropathy will be discussed. Various experimental studies carried out in this regard will be analyzed and discussed.

Most of the preclinical studies based on animal models found that Nigella sativa extract in any form such N. sativa or the powdered form suggest its positive impact on the endocrine system. In particular, N. sativa appears helpful with regard to restoring the healthy histological architecture of endocrine tissue or its active constituents. In a general sense, it has manifested potential to directly remodel/modify their function, mitigating the hormonal disturbances seen in most common endocrine disorders such as thyroid dysfunction, metabolic, adrenal, and gonadal disorders. The therapeutic action of N. sativa is largely contributed by thymoquinone, a monoterpene compound. This monoterpene acts as a molecular scavenger of reactive oxygen species. It protects the endocrine tissue from the free radical species’ damaging effect and contributes in rebalancing hormonal disturbances. More extensive and rigorous preclinical research in combination with clinical studies can unravel the therapeutic properties and features of N. sativa in the context of specific endocrine disorders. At the same time working on technological novelties capable of improving its bioavailability and penetration potential is quite promising, while refining the regulatory framework of this research and its potential clinical implications is necessary.

CRISPR/Cas has become the new face of genome editing with rapidly expanding applications in academic research (reverse genetics and functional genomics), as well as applied research to develop new crop varieties with improved traits. The policies and regulations of CRISPR-edited crops are debated worldwide. For example, the USA has been deregulating CRISPR-edited organisms (CEOs) especially crops under existing regulatory laws, whereas the EU regulates all types of CRISPR-edited crops as genetically modified crops. These crops hold tremendous potential for global agriculture and food security. Therefore, the question of how these crops will be regulated determines the future of CRISPR. In this chapter, we highlight product- and process-based regulations of genetically modified (GM) crops because genome editing regulations are also based on these existing regulations. Also, we discuss that the outcomes of site-directed nucleases (ZFNs, TALENs, and CRISPR/Cas) are sometimes similar to conventional mutagenesis techniques, although the worldwide community is divided over their regulation. The USA has been deregulating site-directed nuclease (SDN1 and SDN2) crops, whereas the EU has been following process-based regulation for genome-edited crops and has classified the outcomes of SDN1, SDN2, and SDN3 as GMOs. Furthermore, we emphasize that there is a need for a new product based-scalable regulatory system for genome-edited crops to face the global challenges of food security, food safety, and sustainable agriculture. We summarize that although CRISPR-edited crops are transgene-free, public acceptance of these crops remains a challenge. We also highlight the ethical issues of CRISPR-edited crops and the importance of governance because scientists have cautioned about CRISPR-based gene drives. We also briefly discuss the regulatory cost and time required for the approval of these crops. Finally, we discuss the future prospects of CEOs and challenges related to their regulation.

Thirty new aryl-pyridazinone-substituted benzenesulphonylurea derivatives (I-XXX) were synthesized and evaluated for their anti-hyperglycaemic activity in glucose-fed hyperglycaemic normal rats. Twenty-three compounds (III-XI, XIV-XVII, XIX-XXIV, XXVI and XXVIII-XXX) showed more or comparable area under the curve (AUC) reduction percentage (ranging from 21.9% to 35.5%) as compared to the standard drug gliclazide (22.0%). On the basis of docking results, 18 compounds were screened for their in vitro ability to inhibit rat lens aldose reductase. Ten compounds (III-VI, XII, XVI-XVIII, XXI and XXVII) showed ARI activity with IC50 ranging from 34 to 242 μM. Out of these, two compounds IV and V showed best ARI activity which is comparable with that of quercetin. As a result, two compounds (IV and V) possessing significant dual action (anti-hyperglycaemic and aldose reductase inhibition) were identified and may be used as lead compounds for developing new drugs.

The chemistry of phthalazine derivatives has been of increasing interest since many of these compounds have found many chemotherapeutic applications. So this study aims to synthesize a library of phthalazine derivatives and to investigate their anti-inflammatory and anti-proliferative activities. Sixteen new phthalazinone derivatives (2a-p) were synthesized and tested for their in vitro antiproliferative and in vivo anti-inflammatory activities. All the synthesized compounds were identified and characterized by IR, (1) H NMR, (13) C NMR spectroscopy, and MS. Two compounds, 2b and 2i, showed significant anti-inflammatory activity comparable with that of the standard drug etoricoxib in the carrageenan-induced rat paw edema model at 3 and 5 h, respectively. Three compounds (2h, 2j, and 2g) showed moderate sensitivity toward the renal cancer cell line UO-31.

Seventeen new pyrazoline substituted benzenesulfonylurea/thiourea derivatives (2a–q) were synthesized and characterized by elemental analysis and various spectroscopic techniques viz; IR, 1H NMR, 13C NMR, and MS data. Thirteen compounds showed moderate to good anti-hyperglycaemic activity in glucose fed hyperglycaemic normal rats at the dose of 0.05 mM/kg b.w. On the basis of docking results nine compounds (2a, 2c, 2e, 2h, 2k, 2l, 2n, 2o and 2q) were evaluated for their ability to inhibit rat lens aldose reductase. Out of these six compounds (2h, 2k, 2l, 2n, 2o and 2q) were found more effective than the known ARI sorbinil. Five compounds (2h, 2k, 2l, 2n and 2o) showed significant dual action (anti-hyperglycaemic and aldose reductase inhibition).

Some new benzenesulfonylthiourea derivatives substituted with phthalazones (2a–q) were synthesized by refluxing the appropriate 4-aryl-1-oxophthalazin-2(1H)yl benzenesulfonamides with isothiocyanate in dry acetone over anhydrous K2CO3. All the synthesized compounds were characterized on the basis of IR, 1H NMR, MS data and elemental analysis. These synthesized compounds (2a–q) at the dose of 20 mg/kg were tested for antihyperglycemic activity in the glucose-fed hyperglycemic normal rat model and among these compounds 2f and 2m showed modest antihyperglycemic activity.

Nine novel 4-[3-(4-Dimethylamino-phenyl)-5-aryl-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamides (2a-i) were synthesized and evaluated for their anti-inflammatory and antiproliferative activities. These compounds (2a-i) showed moderate to strong anti-inflammatory activity in carrageenan rat paw oedema test. Compounds 2b, 2d and 2g showing comparable anti-inflammatory activity to that of reference drug celecoxib were evaluated for their ulcerogenic and analgesic activities. The effect of 2b, 2d and 2g on the content of NO, TNF-α and PGE2 in exudates from rat paw stimulated by carrageenan was also evaluated. The compound 2c showed considerable antitumor activities against all 60 human tumor cell lines with effective GI50 (MG-MID) value of 3.63 µM. It exhibited maximum activity against melanoma (LOX IMVI and SK-MEL-5) cancer cell lines with GI50 value less than 2 μM.

A series of novel pyrazolines (2a–l) bearing benzenesulfonamide moiety were synthesized by condensing appropriate chalcone (1a–l) with 4-hydrazinobenzenesulfonamide hydrochloride. Structure of all novel synthesized compounds was characterized on basis of elemental analysis data and spectral data (IR, 1HNMR, MS). Compounds (2a–l) were screened for in vivo anti-inflammatory action in carrageenan-induced rat paw edema model and blood glucose lowering action in glucose fed hyperglycemic normal rats. Compounds 2a, 2e, and 2l showed significant anti-inflammatory action (more than 75 %) at 5 h and also showed superior gastrointestinal safety profiles as compared to celecoxib. One compound (2i) was found to exhibit significant blood glucose lowering activity.

Absract A series of novel pyridazinone derivatives bearing benzenesulfonamide moiety ( 2a – h ) has been synthesized by the condensation of appropriate aroylacrylic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol. Five derivatives ( 2a , 2b , 2d , 2g and 2h ) were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute. The 2h showed remarkable activity against SR (leukemia) and NCI-H522 (non-small cell lung) with a GI 50 value of less than 0.1 μM. It also displayed good activity against leukemia (CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226), non-small cell lung cancer (NCI-H460), colon (HCT-116, HCT-15, HT29, KMI2, SW-620), CNS (SF-295), melanoma (MALME-3M, M14, MDA-MB-435 SK-MEL-5), ovarian (OVCAR-3, NCI/ADR-RES) and breast (MCF7) cancer cell lines with a GI 50 less than 1.0 μM. The acute toxicity study of 2h indicated that it is well tolerated intra-peritoneally (400 mg/kg) by athymic nude mice. The 2h may possibly be used as lead compound for developing new anticancer agents.

Five (2a–e) benzenesulfonylurea derivatives bearing pyridazinone were synthesized by refluxing the appropriate 6-aryl-2-(p-sulfamylphenyl)-4,5-dihydropyridazine-3(2H)-one with benzylisocyanate in dry acetone over anhydrous K2CO3. These compounds were characterized by elemental analysis and various spectroscopic techniques viz; IR, 1H NMR, 13C NMR, and MS data. These compounds (2a–e) at the dose of 20 mg/kg were tested for blood glucose lowering activity in glucose-fed hyperglycemic normal rats. Compound 2b showed more potent anti-hyperglycemic activity than the standard drug gliclazide. The compound 2b was also tested for its hypoglycemic effect in fasted normal rats. It also showed significant hypoglycemic effect (but less than that of gliclazide).

Some new benzenesulfonylthiourea derivatives substituted with pyridazinone (2a–o) were synthesized by refluxing the appropriate 6-aryl-2-(p-sulfamylphenyl)-4,5-dihydropyridazine-3(2H)-ones with isothiocyanate in dry acetone over anhydrous K2CO3. All the synthesized compounds were characterized on the basis of IR, 1H NMR, 13C NMR, DEPT and MS data, and elemental analysis. These compounds at the dose of 20 mg/kg were tested for blood glucose lowering activity in glucose-fed hyperglycemic normal rats. Five compounds (2a, 2d, 2l, 2m, and 2n) markedly reduced the content of glucose in rat blood (by more than 25%). Compound 2d showed the maximum reduction (38.8%).

The chemistry of phthalazine derivatives has been of increasing interest since many of these compounds have found many chemotherapeutic applications. So this study aims to synthesize a library of phthalazine derivatives and to investigate their anti-inflammatory and anti-proliferative activities. Sixteen new phthalazinone derivatives (2a-p) were synthesized and tested for their in vitro antiproliferative and in vivo anti-inflammatory activities. All the synthesized compounds were identified and characterized by IR, (1) H NMR, (13) C NMR spectroscopy, and MS. Two compounds, 2b and 2i, showed significant anti-inflammatory activity comparable with that of the standard drug etoricoxib in the carrageenan-induced rat paw edema model at 3 and 5 h, respectively. Three compounds (2h, 2j, and 2g) showed moderate sensitivity toward the renal cancer cell line UO-31.

A series of sulfonamide derivatives (2a-l) incorporating substituted pyridazinone moieties were investigated for the inhibition of two human cytosolic carbonic anhydrase isoforms, hCA I and hCA II. All these compounds, together with the clinically used sulfonamide acetazolamide were investigated as inhibitors of the physiologically relevant isozymes I and II. These sulfonamides showed very strong inhibition against all these isoforms with K-I's in the range of 0.98-8.5 nM which makes such molecules possible to be used as leads for discovery of novel effective CA inhibitors targeting other isoforms with medicinal chemistry applications. (C) 2016 Elsevier Ltd. All rights reserved., TUBITAK (The Scientific and Technological Research Council of Turkey) [114Z731], This study was financed by TUBITAK (The Scientific and Technological Research Council of Turkey) (Project no: 114Z731) for (MS).

Twenty six new pyrazoline substituted benzenesulfonylureas (2a–z) were synthesized and tested for in vitro anticancer activity. Fourteen derivatives (2i, 2k–2p, 2r, 2s–2x) were screened for their antiproliferative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). Among them four compounds (2i, 2n, 2v and 2x) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM). The compounds 2i, 2n, 2v and 2x showed effective growth inhibition (GI50 MID) values of 2.62, 3.93, 3.33, 3.74 μM respectively beside cytostatic activity TGI (MG-MID) values of 8.42, 65.80, 24.00 and 36.06 μM respectively. The compound 2i displayed remarkable antiproliferative activity in 8 different cell lines with GI50 less than 2 μM. Compounds 2n, 2v and 2x also displayed good antiproliferative activity against 11, 18 and 14 different cell lines respectively with GI50 less than 3 μM.

The synthesized compounds are tested for their anti-inflammatory and anticancer activities.

Nine 4-arylphthalazones bearing benzenesulfonamide (2a–i) were synthesized by the condensation of the appropriate 2-aroylbenzoic acid (1a–i) and 4-hydrazinobenzenesulfonamide in ethanol. The structures of these compounds were elucidated by elemental analysis, IR, 1H NMR, 13C NMR, and MS spectroscopy. Two compounds, 2b and 2i, showed significant anti-inflammatory activity comparable to that of the standard drug celecoxib in the carrageenan-induced rat paw edema model. These compounds (2b and 2i) had selective inhibitory activity towards the COX-2 enzyme. Compound 2b had a better selectivity ratio (COX-1/COX-2) compared to that of celecoxib and can be used as a novel template for the design of selective COX-2 inhibitors. Compounds 2d and 2i were screened for their antiproliferative activity toward 60 human cancer cell lines by the National Cancer Institute (USA). The compounds 2d and 2i displayed mild activity toward the renal cancer cell line UO-31.

Sixteen new 6-aryl-2-( p -(methanesulfonyl)phenyl)-4,5-dihydropyridazi-3(2 H )-ones ( 2a – p ) were synthesized and tested for in vitro anticancer and in vivo anti-inflammatory activities. Eleven ( 2b , 2d , 2e – j and 2m – p ) of the obtained compounds were screened for their antiproliferative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). Compound 2f showed remarkable activity with GI 50 less than 1 μM on 36 human tumor cell lines and has been referred to Biological Evaluation Committee (NCI) for advance study. Compound 2g also displayed promising antiproliferative activity against 20 different cell lines with GI 50 less than 1 μM. Compounds 2k and 2n were found to have a comparable anti-inflammatory activity to that of standard drug etoricoxib in carrageenan-induced rat hind paw edema model at 5 h.

Novel pyridazones (III) bearing a benzenesulfonamide moiety are synthesized and evaluated for their anticancer activity toward human cancer cell lines.

Some unnatural chalcones (1a-q) and flavones (2a-d) have been synthesized and evaluated for their antiinflammatory activity using carrageenan-induced rat paw edema assay. The flavone 2c (6-Chloro-7-methyl-3', 4'- dimethoxyflavone) had higher anti-inflammatory activity and superior gastrointestinal safety profiles than the reference drug celecoxib. Compound 2c showed almost two times better selective inhibitory activity towards COX-2 enzyme than celecoxib. 2'-Hydroxychalcones (1a-h) showed moderate to strong anti-inflammatory activity (38.6-82.4 % at 3h and 52.4–80.2 % at 5h). Among 2'-methoxychalcones (1i-q) 1k and 1q exhibited maximum activity 82.6% (at 3h) and 84.3% (at 5h) respectively.

Seven novel 6-aryl-2-(p-sulfamoylphenyl)-4,5-dihydropyridazin-3(2H)-ones (2a-g) were synthesized by the condensation of appropriate aroylpropionic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol. Structure of all compounds have been elucidated by elemental analysis, IR, (1)H NMR, (13)C NMR, DEPT and MS spectrscopy. These compounds were tested for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Compound 2b exhibited anti-inflammatory activity comparable to that of celecoxib (at 5 h). Two other compounds 2d and 2g showed promising anti-inflammatory activity (edema reduction more than 80% at 5 h). These compounds (2b, 2d and 2g) did not produce any ulceration in gastric region.

Thirteen new 2-pyrazoline derivatives bearing benzenesulfonamide moiety (2a-m) were synthesized by condensing appropriate chalcones with 4-hydrazinonbenzenesulfonamide hydrochloride and tested for anticancer and anti-inflammatory actions. According to the protocol of the National Cancer Institute (NCI) in vitro disease-oriented human cells screening panel assay compounds 2b, 2c, 2e, 2f and 2g exhibited considerable antitumor activities against the entire tested tumor cell lines and showed effective growth inhibition GI(50) (MG-MID) values of 2.63, 2.57, 6.61, 3.31 and 2.57μM, respectively, beside a cyclostatic activity TGI (MG-MID) 9.54, 8.51, 24.0, 19.9 and 8.71μM, respectively. Two compounds 2g and 2k showed more potent anti-inflammatory activity than celecoxib at 5h in carrageenan-induced rat paw edema bioassay. These compounds (2g and 2k) proved to have superior gastrointestinal safety profiles as compared to celecoxib, when tested for their ulcerogenic effects. Compounds 2g and 2k showed no inhibition against the enzymatic activity of bovine COX-2 (in vitro).