An efficient method for synthesis, characterization and molecular docking study of new sulfamethoxazole derivatives as antibacterial agents.

A new series of sulfamethoxazole derivatives bearing some biologically active heterocycles such as pyrazole (2), 3,4-dihydropyrimidin (3-7, 11, 12), pyrrole (9) and 1,3-dihydropyrimidin (10) rings were successfully synthesized. Identification of designed compounds was done by physicochemical properties and spectral measurements (1H-NMR, 13C-NMR and FT-IR). New prepared derivatives were assay for their (in vitro) antibacterial efficacy against four types of pathogenic bacterial isolates. Significant of the newly prepared compounds appeared promising activity comparison to the cephalexin standard drug. Most of the active compounds are docked into the effective site of tested bacterial enzymes obtained by crystal structure; results reveal the binding template to enzymes of bacteria, which closely related to the laboratory results.

Probing sulphamethazine and sulphamethoxazole based Schiff bases as urease inhibitors; synthesis, characterization, molecular docking and ADME evaluation.

In the current study, a novel series of Schiff base derivatives of (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (3a-3f) and (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (3g-3q) were synthesize. The structures of synthetic compounds were elucidated by various spectroscopic techniques such as FTIR, NMR and spectrometric HRMS analysis. Synthetic derivatives were evaluated for their Jack Bean urease inhibitory activity using established in-vitro assay. It is worth mentioning here that most of our derivatives of both series displayed moderate to strong inhibitory activity, ranging between IC50 = 2.48 ± 0.78 µM and 35.63 ± 1.26 µM, as compared to standard thiourea (IC50 = 20.03 ± 2.03 µM). Further, structure activity relationship studies suggest that the presence of halogen at ortho and para positions on the aryl ring in (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide derivatives and hydroxy and halogen in (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide derivatives increased the urease inhibitory activity. Furthermore, molecular docking studies were carried out in order to investigate the binding mode of this class of compounds to urease. In order to evaluate drug likeness of compounds ADME evaluation was done, and the synthesized compounds were found to be non-toxic and present passive gastrointestinal absorption. The data suggests the synthesized sulphamethazine and sulphamethoxazole derivatives can serve as a novel scaffold to inhibit urease.

Direct incorporation of nano graphene oxide (nGO) into hydrophobic drug crystals for enhanced aqueous dissolution.

This paper reports the development of a successful anti-solvent method that incorporates colloidal nano scale graphene oxide (nGO) directly into hydrophobic drug crystals. The nGO dispersed in solution acted as nucleating sites for crystallization and were embedded into the drug crystals without altering its structure or physical properties such as melting point. Several composites of drugs Sulfamethoxazole and Griseofulvin were synthesized with nGO concentration ranging between 0.2 and 1.0 %. The presence of nGO dramatically enhanced the dissolution rate. The time needed to reach a 50 % release (T50) reduced from 42-14 min with the integration of 0.8 % nGO in SMZ, while in GF the reduction was from 44-27 min with 0.5 % nGO. Increased release rates are attributed to the presence of the hydrophilic nGO which hydrogen bond more so with the aqueous mediums. Therefore, the incorporation of nGO into poorly soluble drugs is an effective approach towards drug delivery and bioavailability improvement and opens a new approach to high performance drug delivery.

Novel Sulfamethoxazole Ureas and Oxalamide as Potential Antimycobacterial Agents.

Infections caused by Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM) are considered to be a global health problem; current therapeutic options are limited. Sulfonamides have exhibited a wide range of biological activities including those against mycobacteria. Based on the activity of 4-(3-heptylureido)-N-(5-methylisoxazol-3-yl)benzenesulfonamide against NTM, we designed a series of homologous sulfamethoxazole-based n-alkyl ureas (C1-C12), as well as several related ureas and an oxalamide. Fifteen ureas and one oxalamide were synthesized by five synthetic procedures and characterized. They were screened for their activity against Mtb. and three NTM strains (M. avium, M. kansasii). All of them share antimycobacterial properties with minimum inhibitory concentration (MIC) values starting from 2 µM. The highest activity showed 4,4'-[carbonylbis(azanediyl)]bis[N-(5-methylisoxazol-3-yl)benzenesulfonamide] with MIC of 2-62.5 µM (i.e., 1.07-33.28 µg/mL). Among n-alkyl ureas, methyl group is optimal for the inhibition of both Mtb. and NTM. Generally, longer alkyls led to increased MIC values, heptyl being an exception for NTM. Some of the novel derivatives are superior to parent sulfamethoxazole. Several urea and oxalamide derivatives are promising antimycobacterial agents with low micromolar MIC values.

Modification of existing antibiotics in the form of precursor prodrugs that can be subsequently activated by nitroreductases of the target pathogen.

The use of existing antibiotics in the form of prodrug followed by activation using enzymes of pathogenic origin could be a useful approach for antimicrobial therapy. To investigate this idea, a common antibiotic, sulfamethoxazole has been redesigned in the form of a prodrug by simple functional group replacement. Upon reductive activation by a type I nitroreductase from a pathogen, the drug displayed enhanced antimicrobial capacity. This strategy could improve the efficacy and selectively of antibiotics and reduce the incidence of resistance.

A Novel Synthesized Sulfonamido-Based Gallate-JEZ-C as Potential Therapeutic Agents for Osteoarthritis.

Gallic acid (GA) and its derivatives are anti-inflammatory agents reported to have an effect on osteoarthritis (OA). However, GA has much weaker anti-oxidant effects and inferior bioactivity compared with its derivatives. We modified GA with the introduction of sulfonamide to synthesize a novel compound named JEZ-C and analyzed its anti-arthritis and chondro-protective effects. Comparison of JEZ-C with its sources i.e. GA and Sulfamethoxazole (SMZ) was also performed. Results showed that JEZ-C could effectively inhibit the IL-1-mediated induction of MMP-1 and MMP-13 and could induce the expression of TIMP-1, which demonstrated its ability to reduce the progression of OA. JEZ-C can also exert chondro-protective effects by promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as evidenced by improved cell growth, enhanced synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Meanwhile, expression of the collagen I gene was effectively downregulated, revealing the inhibition of chondrocytes dedifferentiation by JEZ-C. Hypertrophy that may lead to chondrocyte ossification was also undetectable in JEZ-C groups. The recommended dose of JEZ-C ranges from 6.25×10-7 µg/ml to 6.25×10-5 µg/ml, among which the most profound response was observed with 6.25×10-6 µg/ml. In contrast, its source products of GA and SMZ have a weak effect not only in the inhibition of OA but also in the bioactivity of chondrocytes, which indicated the significance of this modification. This study revealed JEZ-C as a promising novel agent in the treatment of chondral and osteochondral lesions.