The current study aims to assess the use of nanocarriers to limit drug incompatibilities in clinical settings, and thus eliminating serious clinical consequences (e.g., catheter obstruction and embolism), and enhancing in vivo bioavailability and efficacy. As a proof-of-concept, the impact of loading well-documented physically incompatible drugs (i.e., furosemide and midazolam) into nanosized vesicles on in vitro stability and in vivo bioavailability of the two drugs was investigated. Furosemide and midazolam were loaded into nanosized spherical vesicles at high entrapment efficiency (ca. 62–69%). The drug-loaded vesicles demonstrated a sustained drug release patterns, high physical stability and negligible hemolytic activity. Physical incompatibility was assessed by exploiting microscopic technique coupled with image processing and analysis, dynamic light scattering and laser Doppler anemometry. Incorporation of drugs separately inside the nanosized vesicles dramatically decreased size and number of the precipitated particles. In vivo, the niosomal drug mixture demonstrated a significant improvement in pharmacokinetic profiles of furosemide and midazolam compared to the mixed free drug solutions, as evidenced by their longer circulation half-lives and higher area under the plasmaconcentration time curves of both drugs. Nanocarriers could provide an auspicious strategy for circumventing drug incompatibilities, thus reducing adverse reactions, hospitalization period and improving therapeutic outcomes.

In this study, new derivatives of the antitubercular and anti-inflammatory drug, 4-aminosaliclic acids (4-ASA) were synthesized, characterized, and evaluated for these activities. In vivo and in viro evaluation of anti-inflammatory activity revealed that compounds 10, 19 and 20 are the most active with potent cyclooxygenase-2 (COX-2) and 5-lipooxgenase (5-LOX) inhibition and without causing gasric lesions. The minimum inhibitory concentrations (MIC) of the newly synthesized compound were, also, measured against Mycobacterium tuberculosis H37RV. Among the tested compounds 17, 19 and 20 exhibited significant activities against the growth of M. tuberculosis. 20 is the most potent with (MIC 1.04 µM) 2.5 folds more potent than the parent drug 4-ASA. 20 displayed low cytotoxicity against normal cell providing a high therapeutic index. Important structure features were analyzed by docking and structure–activity …

5-Acetyl-3-cyano-6-methyl-4-styryl/(4-methxphenyl)pyridine-2(1H)-thiones (IIa), (IIb) were synthesized via reacting ylidenecyanothioacetamides (Ia), (Ib) with acetylacetone. Treatment of compound (IIa) with certain N-aryl-2-chloroacetamides, under mild basic conditions (sodium acetate trihydrate), gave the expected 2-((5-acetyl-3-cyano-6-methyl-4-styrylpyridin-2-yl)thio)- N-arylacetamides (IIIa–IIIf). Conversion of (IIIa–IIIf) into the corresponding thienopyridines (IVa–IVf) was carrired out in boiling ethanol containing anhydrous sodium carbonate. Reaction of (IVb),(IVf) with 2,5-dimethoxytetrahydrofuran afforded pyrrolylthienopyridines (Vb), (Vf). Cyclocondensation of (IVb), (IVf) with triethyl orthoformate produced pyridiothienopyrimidinones (VIb), (VIf). Diazotization of compounds (IVb–IVd) afforded triazinones (VIIb–VIId). Compound (IIa) was treated with 2-chloromethyl-1H-benzimidazole to afford 2-(((1H-benz[d]imidazol-2-yl)methyl)thio)-5-acetyl-4-(4-methoxy- yphenyl)-6-methylnicotinonitrile (VIII). Cyclization of (VIII) into 1-(3-amino-2-(1H-benz[d]imidazol- 2-yl)thienopyridine (IX) was carried out. Compound (IX) underwent different reactions with some reagents to furnish condensed benzimidazoles (X–XIII). [1,2,3]Triazine (XIV) was synthesized via diazotization of (IX). Some of our target derivatives had been examined in vitro for their antibacterial activities against MRSA and E. coli, and promising results obtained. Most of new styrylpyridines were evaluated for their insecticidal activity towards A. gossypii (Glover, 1887) and considerable results recorded.