Elsayed E. Habib

Non-classical antifolates. Part 2: Synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones

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.

Synthesis, Antimicrobial, and Anti-inflammatory Activities of Novel 5-(1-Adamantyl)-4-arylideneamino-3-mercapto-1,2,4- triazoles and Related Derivatives

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.

Synthesis of novel 6-phenyl-2,4-disubstituted pyrimidine-5-carbonitriles as potential antimicrobial agents

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.

Nonclassical antifolates, part 4. 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiols as a new class of DHFR inhibitors: synthesis, biological evaluation and molecular modeling study.

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.

Synthesis, antimicrobial, and anti-inflammatory activity, of novel S -substituted and N -substituted 5-(1-adamantyl)-1,2,4-triazole-3-thiols

The reaction of 5-(1-adamantyl)-4-phenyl-1,2,4-triazoline-3-thione (compound 5) with formaldehyde and 1-substituted piperazines yielded the corresponding N-Mannich bases 6a–f. The reaction of 5-(1-adamantyl)-4-methyl-1,2,4-triazoline-3-thione 8 with various 2-aminoethyl chloride yielded separable mixtures of the S-(2-aminoethyl) 9a–d and the N-(2-aminoethyl) 10a–d derivatives. The reaction of compound 5 with 1-bromo-2-methoxyethane, various aryl methyl halides, and ethyl bromoacetate solely yielded the S-substituted products 11, 12a–d, and 13. The new compounds were tested for activity against a panel of Gram-positive and Gram-negative bacteria and the pathogenic fungus Candida albicans. Compounds 6b, 6c, 6d, 6e, 6f, 10b, 10c, 10d, 12c, 12d, 12e, 13, and 14 displayed potent antibacterial activity. Meanwhile, compounds 13 and 14 produced good dose-dependent anti-inflammatory activity against carrageenan-induced paw edema in rats.

Synthesis, biological evaluation and molecular modeling study of 2-(1,3,4-thiadiazolyl-thio and 4-methyl-thiazolyl-thio)- quinazolin-4-ones as a new class of DHFR inhibitors

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.

Pyrimidine-5-carbonitriles - part III: synthesis and antimicrobial activity of novel 6-(2-substituted propyl)-2,4-disubstituted pyrimidine-5-carbonitriles

Abstract 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.

Pyrimidine-5-carbonitriles II: Synthesis and Antimicrobial Activity of Novel 6-Alkyl-2,4-disubstituted pyrimidine-5-carbonitriles

New series of 6-alkyl-2,4-disubstituted pyrimidine-5-carbonitriles namely, 6-alkyl-2-thiouracil-5-carbonitriles 4c,d, 6-alkyl-2-arylmethylsulfanyl-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 5a-p, 6-alkyl-2-(2-methoxyethylsulfanyl)-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 6a-d, 6-alkyl-2-benzyloxymethylsulfanyl-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 7a-c, 6-alkyl-2-(5-nitrofuran-2-ylmethylsulfanyl)-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 8a-d, 6-alkyl-4-arylthio-2-(benzylsulfanyl)pyrimidine-5-carbonitriles 10a, b and 2-benzylsulfanyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-6-pentylpyrimidine-5-carbonitrile 11, 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 4d, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5 l, 5p, 7a, 7b, 7c, 8a, 8b, 8c, 8d and 11 -displayed marked antibacterial activity particularly against the tested Gram-positive bacteria. Meanwhile, none of these compounds were proved to be active against Candida albicans.

Synthesis, biological evaluation and molecular modeling study of some new methoxylated 2-benzylthio-quinazoline-4(3H)-ones as nonclassical antifolates.

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 0.01μM, 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 2.4μM, respectively.

Antimicrobial and Hypoglycemic Activities of Novel N-Mannich Bases Derived from 5-(1-Adamantyl)-4-substituted-1,2,4-triazoline-3-thiones

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 > 75%).