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A new hybrid molecule of Benzothiazole cross-linked with hydroxamic acid through an amino acid or aminoalkanoic acid were synthesised. All the synthesized hybrid molecules (1-5) were subjected to molecular docking studies to evaluate their binding affinities with histone deacetylase enzyme (HDAC8, PDB ID: 1T69) and recorded lower ΔG (-8.276, -10.093, -8.647, -6.315, -8.676 kcal/mole, respectively) than the reference ligand (Vorinostat, suberoylanilide hydroxamic acid, SAHA -5.375 kcal/mole). Molecular docking studies were performed using the maestro software (Schrödinger, version 2022-1). Moreover, compound 2, which is Benzothiazole-p-amino benzoic acid-hydroxamate has recorded the lowest binding score (-10.093). This may indicate that this compound is the most potent hybrid molecule. There were no violations from Lipinski’s rule and all the synthesized hybrid molecules comply with all parameters. Swiss ADME server was employed for the in silico molecular docking for prediction of the physicochemical and ADME properties of the investigated compounds. All hybrid molecules showed low possible passive oral absorption and no penetration into BBB. The hybrid molecules 1and 3 may be considered as P-gp substrates.

This study involved the development of innovative compounds consisting of dipeptide cross-links combined with hydroxamic acid. Our objective was to assess their binding affinities with histone deacetylase 8 (HDAC8) by conducting a docking study, comparing the results with the reference ligand, suberoylanilide hydroxamic acid (SAHA). Docking scores were measured in terms of ΔG (Kcal/mol), and the recorded scores for compounds 2A-D were found to be higher than that of SAHA, with values of 87.36, 80.46, 79.42, and 74.14, respectively. Notably, compound 2A, a dipeptide consisting of L-tryptophyl-L-tyrosine linked to a hydroxamic acid moiety, exhibited the highest docking score of 87.36. This finding suggests that compound 2A may possess the most potent HDAC8 inhibitory activity among the other designed compounds. Furthermore, we utilized the SwissADME server to predict the physicochemical properties and additional ADME parameters for the designed compounds. The analysis revealed that all investigated compounds exhibited a high potential for passive oral absorption and demonstrated no penetration into the blood-brain barrier. Compound 2A, 2B, and 2D exhibited one Lipinski's rule violation each, whereas Compound 2C demonstrated no such violations in all parameters. Additionally, compounds 2A and 2C exhibited potential as P-glycoprotein (P-gp) substrates. SAHA did not exhibit inhibition of any of the cytochrome P450 (CYP) enzymes used in this study, whereas compounds 2B, 2C and 2D displayed possible inhibitory activities. These compelling findings provide encouraging prospects for the future synthesis of the designed compounds and warrant further evaluation through in vitro and in vivo biological studies.

New hybrid molecules of Benzothiazole cross-linked with hydroxamic acid through an amino acid or aminoalkanoic acid are suggested. All the synthesized hybrid molecules (2A-E) were subjected to molecular docking to evaluate their binding affinities with histone deacetylase enzyme (HDAC8, PDB ID: 1T69) and recorded lower ΔG (-8.117, -6.322, -8.16, -7.939, - 9.46, respectively) than Vorinostat (suberoylanilide hydroxamic acid, SAHA), as the reference ligand, which recorded a much less value of -5.375, using the Maestro software (Schrödinger, version 2022-1). Moreover, compound 2E, which is Benzothiazole-p-amino benzoic acid-hydroxamate has recorded the lowest binding score (-9.460). This may indicate that this compound is the most active hybrid molecule. There were no violations from Lipinski’s rule and all the synthesized hybrid molecules comply with all parameters. SwissADME server was employed for the in silico molecular docking for prediction of the physicochemical and ADME properties of the investigated compounds. All hybrid molecules showed low possible passive oral absorption and no penetration into BBB. The hybrid molecules 2B and 2D may be considered as P-gp substrates. SAHA does not inhibit any of the CYP enzymes used in this study, while, the hybrid molecules 2B, 2D and 2E have shown possible inhibitory activities.

Levofloxacin carboxamides with certain amino acids were prepared through an amide linkage to the amino acid (glycine, histidine, or serine). These carboxamides were subjected to an in silico molecular docking evaluation on DNA gyrase to predict their antibacterial activity using the GOLD suite. The binding affinities were very significant and encouraged the synthesis of the suggested carboxamides for intensive evaluation. These carboxamides were also subjected to Swiss ADME software to predict their ADME parameters. Levofloxacin carboxamides were prepared in high yield, and their chemical structures were confirmed by spectral analysis, such as 1H-NMR, 13C-NMR and FT-IR spectroscopy. Antibacterial activities were evaluated for the new carboxamides against two G-ve (Klebsiella and P. aeruginosa) and one G+ve (Streptococcus pneumonia) bacteria. When compared to levofloxacin, all of the synthesized carboxamides 1-3 demonstrated good activity against three types of bacteria. These carboxamides showed significant antibacterial activities against S. pneumoniae and lower activities against Klebsiella.

Infections caused by bacteria have a significant impact on public health. Chemical synthesis of new derivatives of cephalexin inked to amino acid (tryptophan or histidine) through an amide bond at the acyl side chain is achieved. This is a new approach of incorporating, tryptophan and histidine into the the primary amino group of cephalexin, in order to provide a bulky group very close to the β-lactam ring. This chemical addition act as isosteric group to the alkoximino that protect beta lactam ring from bacterial beta lactamase enzyme. The new derivatives may show resistance to β-lactamases, improve activity and pharmacokinetic properties and may give new life for old drugs that are susceptible to hydrolysis by most β-lactamases. The chemical structures of these derivatives were confirmed by: FTIR, 1H-NMR spectroscopy, elemental micro analysis and some physical properties. Molecular docking on serine beta lactamase and prediction of ADME parameters were recorded using GOLD suite and Swiss ADME software respectively. Docking scores of the new derivatives of Cephalexin on β-lactamases were higher than those of Cephalexin, which may indicate better activity

Certain cyclic amine derivatives of metronidazole via acetate spacer were prepared. Cyclic amines used are piperidine and piperazine to improve the physicochemical properties and reduce some of metronidazole side effects. This is believed to be done by modification of its structural features to get prodrugs with improved properties over that of metronidazole. The present work includes esterification of metronidazole with choroacetic acid, N-alkylation of the cyclic amines by the halogenated ester and characterization of their structures by spectral(UV and IR) and elemental(CHN)analysis.The melting points, degree of solubilities and partition coefficients were also determined. Both metronidazole-piperazine and metronidazole-piperidine derivatives have different structural and physicochemical properties that may be excellent to diminish problems associated with metronidazole. Key words: Metronidazole, chloroacetate, prodrug.

Five new ceftazidime derivatives were designed and synthesized in an attempt to improve the acid stability and may increase the spectrum of ceftazidime. The synthesized compounds included; Schiff base of ceftazidime (compound 1), ceftazidime lysine amide Schiff base (compound 2), ceftazidime lysine amide (compound 3), ceftazidime-di-lysine amide Schiff base (compound 4) and ceftazidime-di-lysine amide (compound 5). New ceftazidime derivatives were successfully prepared characterized and identified using spectral and elemental microanalysis (CHNS) analyses and the results comply with the calculated measurements. Compounds 1 and 2 were subjected to a stability study in phosphate buffer (0.2M, pH 7.4) and in KCl/HCl buffer (0.2M, pH 1.2) at different time intervals (0 – 240 min) incubated at 37 °C. This revealed that both compounds in phosphate buffer (0.2M, pH 7.4) are significantly stable with t 1/2 of 18hrs and 24hrs respectively. However, compounds 1 and 2 are less stable in KCl/HCl buffer (0.2M, pH 1.2) with t1/2 of 3.48hrs and 3.13hrs respectively. The antibacterial evaluation of the new ceftazidime derivatives showed various degrees of antibacterial activities when compared with ceftazidime. The chemical modifications of ceftazidime showed slight effect on activities and most of compounds retained the antibacterial activities. Compounds 2 and 4 afforded comparable antibacterial action. However, compounds 3 and 5 were equipotent with ceftazidime with respect to E.coli and Staph. aureose. Compound 4 has better activity than ceftazidime with respect to Pseudomonas aeruginosa. Schiff's base derivative of lysine (2, 6-bis-(benzylideneamino) hexanoic acid) gave a reasonable antibacterial action towards Escherichia coli and Streptococcus Spp; as compared with lysine which has no antibacterial activity. Key words: Ceftazidime, Schiff bases, Lysine.

The development of new cephalosporins with improved activity against resistant microbes, such as, MRSA (methicillin resistant Staph. aureus), P. aeruginosa, is of high potential. Chemical synthesis of two new series of thiadiazole linked to cysteine (series 1) and cephalosporins containing thiadiazole linked to cysteine through disulfide bond (series 2) were achieved. The chemical structures of the synthesized compounds were confirmed using spectral (FT-IR, 1H-NMR) and elemental microanalysis. The incorporation of privileged chemical moieties, such as, thiadiazole, Schiff base, cysteine and sulfonamide, has been found to have great contribution to the antimicrobial activities. Compounds of series 1 (1b-d), containing a Schiff base or a sulfonamido moiety, showed reasonable activity and were less potent than cephalexin with respect to E. coli and Staph. aureus. The new cephalosporins (series 2) showed remarkable activities on E. coli (62.5-15.6µg/ml) and staph. aureus (31.2-62.5µg/ml) when compared with cephalexin (250 and 125 µg/ml) respectively. Moreover, compounds 1 and 3 showed very promising activity against MRSA (250 and 500µg/ml) respectively. The incorporation of a sulfonamido moiety to the cephalosporin molecule was successfully achieved. This is a very interesting finding which may open a new approach in the synthesis of newer cephalosporins. Keywords: Cephalosporins, Cysteine, Schiff base, Sulfonamides, Thiadiazole.

There is a continuous and massive need for newer cephalosporins that should have resistance against β-lactamases and can be used orally. An approach of using cephalexin, as a well-studied and potent antibacterial compound is considered to prepare new designed derivatives. These derivatives include the incorporation of amino acid moiety linked through an amide bond with the α-amino group of cephalexin. Certain aliphatic amino acids were used, such as glycine, alanine, valine and proline. The chemical structures of these derivatives were confirmed by IR spectroscopy and elemental analyses. All the synthesized compounds were subjected for preliminary evaluation of antimicrobial activity using well diffusion method, against certain microbes. Most of the synthesized compounds were found to possess significant antibacterial activities. Compound 1 (125 μg and 250μg) showed significant activity against P. aeruginosa. Compound 2 (125 and 250μg) exhibited significant activity against P. aeruginosa and Bacillus cereus. Compound 3 (125 and 250μg) demonstrated very significant activity against E. coli, P. aeruginosa and Bacillus cereus and slight activity towards S. aureus. Compound 4 (250μg) showed significant activity against P. aeruginosa and no antibacterial activities against E. coli, S. aureus and Bacillus cereus, as compared with cephalexin as the standard compound. Keywords: Cephalosporins, Cephalexin, Glycine, Alanine, Valine, Proline.

The development of new cephalosporins with improved activity against resistant microbes, such as, MRSA (methicillin resistant Staph. aureus), P. aeruginosa, is of high potential. Chemical synthesis of two new series of thiadiazole linked to cysteine (series 1) and cephalosporins containing thiadiazole linked to cysteine through disulfide bond (series 2) were achieved. The chemical structures of the synthesized compounds were confirmed using spectral (FT-IR, 1H-NMR) and elemental microanalysis. The incorporation of privileged chemical moieties, such as, thiadiazole, Schiff base, cysteine and sulfonamide, has been found to have great contribution to the antimicrobial activities. Compounds of series 1 (1b-d), containing a Schiff base or a sulfonamido moiety, showed reasonable activity and were less potent than cephalexin with respect to E. coli and Staph. aureus. The new cephalosporins (series 2) showed remarkable activities on E. coli (62.5-15.6µg/ml) and staph. aureus (31.2-62.5µg/ml) when compared with cephalexin (250 and 125 µg/ml) respectively. Moreover, compounds 1 and 3 showed very promising activity against MRSA (250 and 500µg/ml) respectively. The incorporation of a sulfonamido moiety to the cephalosporin molecule was successfully achieved. This is a very interesting finding which may open a new approach in the synthesis of newer cephalosporins. Keywords: Cephalosporins, Cysteine, Schiff base, Sulfonamides, Thiadiazole.