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Ciprofloxacin biodegradable implantable matrices (CPX-IMs) of tailored porous surfaces were fabricated by hot melt injection molding of poly-l-lactic acid (PLLA) followed by coating with PLLA/sodium chloride. CPX-IDs were designed to have a non-porous coat (NPC) or a porous coat of small pore size (SPC; 150-250 µm) or a large pore size (LPC; 250-350 µm). CPX-IMs surface pore size was confirmed by scanning electron microscope. The hardness of NPC, LPC, and SPC CPX-IMs were 58 ± 2.8, 53 ± 1.9, and 50 ± 2.1 N, respectively. The measured porosity values were 41.2 ± 1.53, 65.2 ± 1.1, and 60.7 ± 1.2%, respectively. Differential scanning calorimetry was employed to study the compatibility of ingredients, the effect of injection molding on polymer properties, and implants degradation. Coating of CPX-IMs prolonged drug release to reach a value of 90% release in 40 days. Antibacterial activity tests showed sufficiency of CPX to inhibit pathogens known to cause osteomyelitis. The in vivo study showed tissue compatibilities of the inserted matrices in tested rats with no sign of infection throughout the experiment period. SPC and LPC CPX-IMs demonstrated a better osteointegration, cell adhesion, and infiltration of different types of bone cells within implants structure compared to the non-porous matrix. Furthermore, LPC CPX-IMs showed a superior bone cell attachment and osteointegration relative to SPC CPX-IMs. Findings of this study confirmed the impact of porosity and pore sizes on cell proliferation and fracture healing concurrently with the sustained local antibiotic therapy for treatment or prevention of osteomyelitis.

A new series of 2,3,6-substituted-quinazolin-4-ones was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 28 and 61 proved to be active DHFR inhibitors with IC50 0.02 and 0.01 μM, respectively. Molecular modeling studies concluded that recognition with the key amino acid Phe34 is essential for binding and hence DHFR inhibition. Compounds 34, 56 and 66 showed broad spectrum antimicrobial activity comparable to Gentamicin and Ciprofloxacin. Compounds 40 and 64 showed broad spectrum antitumor activity toward several tumor cell lines and proved to be 10 fold more active than 5-FU, with GI50 MG-MID values of 2.2 and 2.4 μM, respectively.

A series of novel 2-Amino-4-Methylthiazole analogs were developed via three-step reaction encompassing hydrazine-1-carboximidamide motif to combat Gram-positive and Gram-negative bacterial and fungal infections. Noticeably, the thiazole-carboximidamide derivatives 4a-d displayed excellent antimicrobial activity and the most efficacious analogue 4d with MIC/MBC values of 0.5 and 4 μg/mL, compared to reference drugs with very low toxicity to mammalian cells, resulting in a prominent selectivity more than 100 folds. Microscopic investigation of 4d biphenyl analogue showed cell wall lysis and promote rapid bactericidal activity though disrupting the bacterial membrane. In addition, an interesting in vitro investigation against GlcN-6-P Synthase Inhibition was done which showed potency in the nanomolar range. Meanwhile, this is the first study deploying a biomimicking strategy to design potent thiazole-carboximidamides that targeting GlcN-6-P Synthase as antimicrobial agents. Importantly, Molecular modeling simulation was done for the most active 4d analogue to study the interaction of this analogue which showed good binding propensity to glucosamine binding site which support the in vitro data.

New dithiocarbamate chalcone-based derivatives were synthesized, their structures were elucidated using different spectroscopic techniques. They were subjected to antimicrobial screening against selected Gram negative bacteria focusing on microbial resistance. Bacterial resistance was targeted via phosphoethanolamine transferase enzyme. Most of the synthesized compounds showed equal or higher activity to colistin standard. Compound 24 proved to be the most active candidate with MIC of 8 µg/ml against both Ps12 and K4 and MBC of 32 µg/ml against Ps12 and 16 µg/ml against K4 Molecular docking study showed that 20, 22, 24 and 25 had good binding affinity with active site residues via Thr280. DNA macromolecule was further targeted. Compounds 28 and 34 were recorded to have better DNA binding than doxurubucin with IC50 of 27.48 and 30.97 µg/ml respectively, suggesting that it could have a role in their higher antibacterial effect. Their docking into DNA has shown a clear intercalation matching with antibacterial data. Pharmacokinetics parameters of active compounds showed that they have better absorption through GIT.

The reaction of 5-(1-adamantyl)-4-ethyl or allyl-1,2,4-triazoline-3-thione with formaldehyde solution and various 1-substituted piperazines yielded the corresponding N-Mannich bases. The newly synthesized N-Mannich bases were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Six compounds showed potent antibacterial activity against one or more of the tested microorganisms, while two compounds exhibited moderate activity against the tested Gram-positive bacteria. None of the newly synthesized compounds were proved to possess marked activity against Candida albicans. The oral hypoglycemic activity of six compounds was determined in streptozotocin (STZ)-induced diabetic rats. Four compounds produced significant strong dose-dependent reduction of serum glucose levels, compared to gliclazide at 10 mg/kg dose level (potency ratio &gt, 75%).

A new series of 2-(1,3,4-thiadiazolyl- or 4-methyl-thiazolyl)thio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 29, 34, and 39 proved to be the most active DHFR inhibitors with IC50 values range of 0.1-0.6 μM. Compounds 28, 31 and 33 showed remarkable broad-spectrum antimicrobial activity comparable to the known antibiotic Gentamicin. Compounds 26, 33, 39, 43, 44, 50, 55 and 63 showed broad spectrum antitumor activity with GI values range of 10.1-100%. Molecular modeling study concluded that recognition with key amino acid Glu30, Phe31 and Phe34 is essential for binding. ADMET properties prediction of the active compounds suggested that compounds 29 and 34 could be orally absorbed with diminished toxicity.

The reaction of 6-(2-methylpropyl or 2-phenylpropyl)-2-thiouracil-5-carbonitriles (4a,b) with various arylmethyl halides, 2-bromoethyl methyl ether, benzyl chloromethyl ether, and 2-bromomethyl-5-nitrofuran in N,N-dimethylformamide or acetone yielded the corresponding substituted thio-3,4-dihydro-4-oxopyrimidine-5-carbonitrile analogues 5a–h, 6a,b, 7, and 8a,b, respectively. Treatment of 5c with phosphorus oxychloride and N,N-dimethylaniline yielded the 4-chloropyrimidine derivative 9, which was allowed to react with various arylthiols, arylamines, and 1-substituted piperazines to yield the respective 4-arylthio 10a–d, 4-arylamino 11a–d, and 4-piperazino 12a,b derivatives. The newly synthesized compounds were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 5e, 5f, 5g,h, 7, 8a,b, and 12a display marked antibacterial activity, particularly against the Gram-positive bacteria. None of these compounds are active against C. albicans.

New 1-adamanyl-1,3,4-thiadiazole derivatives namely, 5-(1-adamantyl)-1,3,4-thiadiazoline-2-thione 3 , 5-(1-adamantyl)-3-(benzyl- or 4-substituted benzyl)-1,3,4-thiadiazoline-2-thione 4a–d , 5-(1-adamantyl)-3-(4-substituted-1-piperazinylmethyl)-1,3,4-thiadiazoline-2-thiones 5a–c , 2-[5-(1-adamantyl)-2-thioxo-1,3,4-thiadiazolin-3-yl]acetic acid 7 , (±)-2-[5-(1-adamantyl)-2-thioxo-1,3,4-thiadiazolin-3-yl]propionic acid 9 , 3-[5-(1-adamantyl)-2-thioxo-1,3,4-thiadiazolin-3-yl]propionic acid 11 , N -[5-(1-adamantyl)-1,3,4-thiadiazol-2-yl]- N ′-arylthioureas 15a–c and 5-(1-adamantyl)-1,3,4-thiadiazoline-2-one 16 , were synthesized and tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans . Compounds 7 , 9 , 15b and 15c displayed marked activity against the tested Gram-positive bacteria, while compound 3 was highly active against the tested Gram-negative bacteria. Compounds 4b , 7 and 15c were weakly or moderately active against C. albicans . In addition, the in vivo anti-inflammatory activity of the synthesized compounds was determined using the carrageenan-induced paw oedema method in rats. The propionic acid derivative 9 produced good dose-dependent anti-inflammatory activity.

A new series of 2,6-substituted-quinazolin-4-ones was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 22, 33-37, 39-43, and 45 proved to be active DHFR inhibitors with IC(50) range of 0.4-1.0microM. Compound 18 showed broad-spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compounds 34 and 36 showed antitumor activity at GI(50) (MG-MID) concentrations of 11.2, and 24.2microM, respectively. Molecular modeling study including flexible alignment; electrostatic, hydrophobic mappings; and pharmacophore prediction were performed. A main featured pharmacophore model was developed which justifies the importance of the main pharmacophoric groups as well as of their relative distances. The substitution pattern and spatial considerations of the pi-systems in regard to the quinazoline nucleus proved critical for biological activity.

The reaction of 1-adamantyl isothiocyanate 4 with the various cyclic secondary amines yielded the corresponding N-(1-adamantyl)carbothioamides 5a–e, 6, 7, 8a–c and 9. Similarly, the reaction of 4 with piperazine and trans-2,5-dimethylpiperazine in 2:1 molar ratio yielded the corresponding N,N'-bis(1-adamantyl)piperazine-1,4-dicarbothioamides 10a and 10b, respectively. The reaction of N-(1-adamantyl)-4-ethoxycarbonylpiperidine-1-carbothioamide 8c with excess hydrazine hydrate yielded the target carbohydrazide 11, in addition to 4-(1-adamantyl)thiosemicarbazide 12 as a minor product. The reaction of the carbohydrazide 11 with methyl or phenyl isothiocyanate followed by heating in aqueous sodium hydroxide yielded the 1,2,4-triazole analogues 14a and 14b. The reaction of the carbohydrazide 11 with various aromatic aldehydes yielded the corresponding N'-arylideneamino derivatives 15a–g. The compounds 5a–e, 6, 7, 8a–c, 9, 10a, 10b, 14a, 14b and 15a–g were tested for in vitro antimicrobial activity against certain strains of pathogenic Gram-positive and Gram-negative bacteria and the yeast-like fungus Candida albicans. The compounds 5c, 5d, 5e, 6, 7, 10a, 10b, 15a, 15f and 15g showed potent antibacterial activity against one or more of the tested microorganisms. The oral hypoglycemic activity of compounds 5c, 6, 8b, 9, 14a and 15b was determined in streptozotocin (STZ)-induced diabetic rats. Compound 5c produced significant reduction of serum glucose levels, compared to gliclazide.

Streptomyces microflavus strain No. 2445 produces many derivatives of fattiviracin antibiotics. The major product of these derivatives is fattiviracin FV-8, which consists of four glucose and two trihydroxy fatty acid residues. We found that this strain has the ability to convert several sugars in the culture medium to glucose, and the glucose added to the medium is directly incorporated into the FV-8 molecule. Two trihydroxy fatty acid residues in the FV-8 molecule are derived from acetic acid, and production of FV-8 is inhibited by the addition of cerulenin, which is an inhibitor of fatty acid biosynthesis.

A new series of compounds possessing 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol skeleton was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, antitumor and schistosomicidal activities. Four active compounds were allocated, the antibacterial 22 (comparable to gentamicin and ciprofloxacin), the schistosomicidal 29 (comparable to praziquantel), the DHFR inhibitor 34 (IC50 0.03 μM, 2.7 fold more active than MTX), and the antitumor 36 (comparable to doxorubicin). Molecular modeling studies concluded that recognition with key amino acid Leu4 and Val1 is essential for DHFR binding. Flexible alignment and surface mapping revealed that the obtained model could be useful for the development of new class of DHFR inhibitors.

The reaction of 5-(1-adamantyl)-4-substituted-1,2,4-triazoline-3-thione 5a,b and 10a,b with formaldehyde solution and various primary aromatic amines or 1-substituted piperazines yielded the corresponding N-Mannich bases 6a-o, 7a-g and 11a-i. The newly synthesized N-Mannich bases 6a-o, 7a-g and 11a-i were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. The compounds 6j, 6l, 6m, 7a, 7b, 7c, 7d, 7f, 11a, 11b, 11c, 11d, 11e, 11f, 11h and 11i displayed moderate to good activity against the tested Gram-positive bacteria, while compounds 7c, 11c, 11d, 11f and 11h showed potent broad spectrum antibacterial activity. None of the newly synthesized compounds were proved to possess marked activity against C. albicans.

A new series of 2-heteroarylthio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 21, 25, and 39 proved to be active DHFR inhibitors with IC50 range of 0.3–0.8 μM. Compounds 25, 28, 33, 35 and 36 showed broad spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compound 29 showed broad spectrum antitumor activity toward several tumor cell lines with GI values range of 25.8–41.2%. Molecular modeling studies concluded that recognition with key amino acid Arg38 and Lys31 are essential for binding and biological activities. Flexible alignment; electrostatic and hydrophobic mappings revealed that the obtained model could be useful for the development of new DHFR inhibitors.

New series of 6-phenyl-2,4-disubstituted pyrimidine-5-carbonitriles namely, 2-substitued thio-6-phenyl-3,4-dihydro-4-oxopyrimidine-5-carbonitriles (5a-d, 6, 7a-d, 8), 2-(4-chlorobenzylthio)-4-chloro-6-phenylpyrimidine-5-carbonitrile (9), 2-(4-chlorobenzylthio)-4-arylthio-6-phenylpyrimidine-5-carbonitriles (10a-d) and 2-(4-chlorobenzylthio)-4-arylamino-6-phenylpyrimidine-5-carbonitriles (11a-d) was synthesized and tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 5b, 5c, 6, 7a, 7b, 7c, 9 and 11a displayed marked antibacterial activity particularly against the tested Gram-positive bacteria, while compounds 6, 7c, 7d and 9 were moderately or weakly active against C. albicans.

The reaction of 5-(1-adamantyl)-4-amino-3-mercapto-1,2,4-triazole (5) with various aromatic aldehydes in ethanol or acetic acid yielded the corresponding 4-arylideneamino derivatives 6a-v. Treatment of the 4-(2,6-difluoro- and dichlorobenzylideneamino) derivatives 6o and 6q with 1-substituted piperazines, and formaldehyde solution in ethanol afforded good yields of the corresponding 5-(1-adamantyl)-4-(2,6-dihalobenzylideneamino-2-(4-substituted-1-piperazinylmethyl)-1,2,4-triazoline-3-thiones 7a-p. 5-(1-Adamantyl)-4-arylideneamino-2-(4-ethoxycarbonyl-1-piperidylmethyl)-1,2,4-triazoline-3-thiones 8a-n, were similarly prepared via the reaction of the corresponding arylideneamino derivative with ethyl 4-piperidinecarboxylate and formaldehyde solution in ethanol. Compounds 6a-v, 7a-p and 8a-n were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Several derivatives showed good or moderate activities, particularly against the tested Gram-positive bacteria. In addition, the in vivo anti-inflammatory activity of 21 compounds was determined using the carrageenan-induced paw oedema method in rats. Compounds 7d, 7g, 7i, 7j, 7l, 8c, 8e and 8l showed good or moderate dose-dependent activity in this area.

Reaction of 1-adamantanecarbonyl chloride with certain carboxylic acid hydrazides in pyridine yielded the corresponding N-acyl adamantane-1-carbohydrazide derivatives 3a-j, which were cyclized to the corresponding 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles 4a-j via heating with phosphorus oxychloride. Treatment of 1-adamantylisothiocyanate with some carboxylic acid hydrazides in ethanol yielded the corresponding 1-acyl-4-(1-adamantyl)-3-thiosemicarbazides 7a-g, which were cyclized to the corresponding 2-(1-adamantylamino)-5-substituted-1,3,4-thiadiazole derivatives 8a-g. Compounds 4a-j, 7a-g, and 8a-g were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Several derivatives produced good or moderate activities particularly against the tested Gram-positive bacteria Bacillus subtilis. Meanwhile, compounds 4i and 8g displayed marked antifungal activity against C. albicans. In addition, the in vivo anti-inflammatory activity of the synthesized compounds was determined using the carrageenin-induced paw oedema method in rats. The oxadiazole derivatives 4c, 4g, 4i and 4j produced good dose-dependent anti-inflammatory activity.

A novel antiviral agent, fattiviracin FV-8, purified from the culture broth of Streptomyces microflavus strain No. 2445, showed potent antiviral activities against human immunodeficiency virus type 1 (HIV-1), herpes simplex virus type 1 (HSV-1), varicella-zoster virus (VZV), and influenza A and B viruses. The action mechanism of fattiviracin FV-8 against HIV-1 was examined. As a result, the agent was thought to act on HIV-1 particles directly without lysis of the particles, and it affords the inhibition of viral entry into the host cells.