Mohammed Samim

Synthesis and evaluation of anticancer activity of some novel 6-aryl-2-(p-sulfamylphenyl)-pyridazin-3(2H)-ones.

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.

Synthesis and evaluation of some new pyrazoline substituted benzenesulfonylureas as potential antiproliferative agents.

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.

Enhancement in the Neuroprotective Power of Riluzole Against Cerebral Ischemia Using a Brain Targeted Drug Delivery Vehicle.

Riluzole is the only available drug for motor neuron diseases quite well-known for its neuroprotective activity. But its poor aqueous solubility, short half-life with some side-effects at higher concentration poses a limitation to its use as a therapeutic agent. The present study was performed to investigate the therapeutic potential of nanoriluzole (NR), i.e., riluzole encapsulated in nanoparticles against cerebral ischemia (stroke) at three different concentrations [10 (NRL), 20 (NRM), and 40 (NRH) μg/kg body weight intraperitoneally (i.p.)]. Chitosan conjugated NIPAAM (N-isopropylacrylamide) nanoparticles coated with tween80 were synthesized through free radical polymerization. The particles were characterized with Transmission Electron Microscopy, Dynamic Light Scattering, and Fourier Transform Infrared spectroscopy and were found to have size of ∼50 nm. Cerebral ischemia was induced by Middle Cerebral Artery Occlusion (MCAO) model for 1 h and NR was given intraperitoneally after 1 h of MCAO. Animals were dissected after a reperfusion period of 24 h for evaluation of various parameters. Triphenyl tetrazolium chloride staining shows substantial reduction in infarct size in all three treated groups. It was also supported by histopathological results, biochemical parameters, and behavioral studies. Immunological parameters like NOS-2, NF-kB, and COX-2 also show profound reduction in expression in NR treated groups. Thus, the present work clearly demonstrated that the nanoparticle was good enough to carry large amount of drug across the Blood Brain Barrier which results in significant neuroprotection even at a very low concentration. It also substantially lowered the required concentration by overcoming the poor aqueous solubility; hence hardly leaving any scope for side-effects.

Pyridazinone substituted benzenesulfonamides as potent carbonic anhydrase inhibitors.

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.

Synthesis and biological evaluation of some new pyrazoline substituted benzenesulfonylurea/thiourea derivatives as anti-hyperglycaemic agents and aldose reductase inhibitors.

Seventeen new pyrazoline substituted benzenesulfonylurea/thiourea derivatives (2a-q) were synthesized and characterized by elemental analysis and various spectroscopic techniques viz; IR, (1)H NMR, (13)C 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).

Synthesis and anti-inflammatory activity of celecoxib like compounds

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.

Size- and shape-dependent clinical and mycological efficacy of silver nanoparticles on dandruff

Dandruff is a prominent scalp problem caused by the growth of fungus Malassezia furfur, potentially cascading into dermal inflammation, itching, and tissue damage. The present work outlines a detailed analysis of the treatment of scalp infection using silver nanomaterials (Ag NMs), and focuses on biocidal activity owing to manipulation of size, shape, and structure. Monodisperse silver spherical nanoparticles (NPs) and nanorods (NRs) were synthesized by chemical routes that were characterized using analytical and spectroscopic techniques. Ag NMs demonstrated enhanced biocidal tendencies compared to market available drugs, itracanozole and ketoconazole, showing greater zones of inhibition. The obtained 20 nm and 50 nm spherical-shaped NPs and 50 nm NRs showed concentration-, size-, and shape-dependent antifungal activity, with 20 nm spherical-shaped NPs exhibiting excellent potency. Minimum inhibitory concentration for 20 nm was lowest at 0.2 mg/mL in comparison to 0.3 mg/mL for NRs. Primary irritation index was 0.33 and 0.16 for 20 nm and 50 nm spherical-shaped NPs, respectively, while 50 nm rod-shaped NMs exhibited negligible redness. An in vivo model for M. furfur infection was generated by passing fungi subcutaneously in rats’ skin. Again, 20 nm particles showed best normalization of skin after 10 days on regular dosing, in comparison with bigger and rod-shaped particles. The statistical clinical score was highest for Ag nanorods, followed by 50 nm Ag NPs-treated animals. It was observed that 20 nm spherical particles exhibited the lowest score (0) compared with others as well as with antifungal drugs. Biochemical analysis performed by checking antioxidant enzymatic activities indicated tissue repair and normalization of enzymes and protein concentration by Ag NPs.

Synthesis and Biological Evaluation of New Phthalazinone Derivatives as Anti-Inflammatory and Anti-Proliferative Agents

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, 1H NMR, 13C 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.

Synthesis and biological evaluation of 4-arylphthalazones bearing benzenesulfonamide as anti-inflammatory and anti-cancer agents.

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.

Design and synthesis of pyridazinone-substituted benzenesulphonylurea derivatives as anti-hyperglycaemic agents and inhibitors of aldose reductase – an enzyme embroiled in diabetic complications

Abstract 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.