Despite enormous efforts have been made in the hunt for new drugs, tuberculosis (TB) still remains the first bacterial cause of mortality. Though this drug has good antitubercular activity, it needs 24 weeks of . to study the structure function relationship for antitubercular activity. Thirty analogues of reported antitubercular CD59 were prepared by two-step synthetic when considering the very limited number of validated targets for TB drug to investigate the structure- activity relationship (SAR) of the lead compound.
It has no cross resistance to the available tuberculosis agents. Though this drug has good antitubercular activity, it needs 24 weeks of treatment thereby encouraging the development of resistance specie arising from noncompliance to prescription and it has also been shown to cause adverse effects like hemoptysis and anorexia [ 23 ].
Delamanid marketed as Deltyba is also indicated for use as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.
It must be administered as directly observed therapy DOT because of its adverse effect and it lasts for 24 weeks. There has been no established safe dosage for patients with renal or hepatic impairment and children or adolescents [ 24 ].
In an effort to discover new and effective chemotherapeutic agent for the treatment of TB, the antimycobacterial activities of various phthalazinyl acetamides [ 25 ], thiazolylthiosemicarbazones [ 26 ], chromeno[3,2-c]pyridineyl derivatives [ 27 ], 1,4 -thiazines [ 28 ], thieno-[2,3-b]thiophene [ 29 ], spirocyclohexanones derivatives [ 30 ], thieno[3,2-b]indoles [ 31 ], furanyl derivatives [ 32 ], thiadiazoles derivatives [ 33 ], imidazole derivatives [ 3435 ], acyclic deoxy monosaccharide derivatives [ 36 ], benzoic acid hydrazine class [ 37 ], calanolide A, a naturally occurring coumarin derivatives [ 3839 ], purine derivatives [ 4041 ], pyrrole derivatives [ 4243 ], benzoxazine derivatives [ 44 ], diterpenoids derived from plants [ 4546 ], and quinoline and quinoxaline derivatives [ 47 ] have been reported.
Synthesis of Pyrazine Derived Carboxamides Pyrazine carboxamide is an important component in the intensive phase of short-course treatment of TB owing to its sterilizing effect, ability to act in acidic environments, and excellent synergy with rifampicin.
They proposed the formation of centrosymmetric dimer pairs with the peptidic carboxamido group of some peptides needed for binding to the receptor site possibly by hydrogen bond formation. The target compounds were synthesized by microwave assisted coupling reaction of methyl ester of substituted pyrazine carboxylic acids 2 with ring substituted benzylamines 3 which yielded series of substituted N-benzyl pyrazinecarboxamides 4a—j Scheme 1.
They used hydrophobic electron withdrawing halogensalkyl substituents on the pyrazine methyl, t-butyland their combination of substituents alkyl, alkoxy, acetyl, OH, and halogens on benzene part. Synthesis of pyrazine carboxamides. The antimycobacterial evaluation of the compounds showed no improvement in comparison with pyrazinamide.
Dole al et al. They achieved this by reacting pyrazinecarboxylic, 6-chloropyrazinecarboxylic, 5-tert-butylpyrazinecarboxylic, or 5-tert-butylchloropyrazinecarboxylic acid, respectively, 50 mmol with thionyl chloride 5.
They removed the excess thionyl chloride by repeated evaporation with dry toluene in vacuo. The crude acyl chloride 5 dissolved in dry acetone 50 mL was added drop wise to a stirred solution of the corresponding substituted amine 6 50 mL and pyridine 50 mmole in dry acetone 50 mL kept at room temperature. After the addition was completed, stirring was continued for 30 min, and then the reaction mixture was poured into cold water mL and the crude amide was collected and purified by the column chromatography Scheme 2.
Synthesis of new derivatives of pyrazine carboxamides. The antimycobacterial activity screening of the twelve compounds showed that several novel derivatives had relatively higher activity against M. They also carried out antimycobacterial evaluation at the tuberculosis antimicrobial acquisition and coordinating facility TAACF program.
Synthesis and Structural Activity Relationship Study of Antitubercular Carboxamides
In the SAR, the importance of iodine substitution in position 3 of benzene ring for the antimycobacterial activity was identified, mostly in compounds 7i and 7l. The discrepancy between the results of two antimycobacterial assays was explained by using different laboratory conditions pH, growth medium.
Acidic pH pH 5. SAR of tetrahydropyrazolopyrimidine carboxamides. A mixture of 2-hydroxynaphthaldehyde 8ethyl bromoacetate, and anhydrous potassium carbonate was heated under reflux for The reaction mixture was filtered and potassium carbonate was washed with acetone which was evaporated to get carboxylate 9. To this point, hydrazine hydrate and ethanol were added and refluxed for The excess ethanol was distilled off to get the respective carbohydrazide The carbohydrazide 10 was mixed with a solution of various substituted aromatic aldehydes 11 in ethanol in DMF.
The reaction mixture was refluxed for 8. To the carboxamide 12 in 1,4-dioxane, mercaptoacetic acid and catalytic amount of anhydrous zinc chloride were added. The mixture was refluxed for 4. Synthesis of naphthofuran carboxamides. The antitubercular activities of the compounds were assessed against M. MIC of naphthofuran carboxamides. Synthesis of N,N-Diaryl 4,5-dichloroimidazoleyl -1,4-dihydro-2,6-dimethyl-3,5-pyridine Dicarboxamides The dihydropyridines DHPs are well known drugs for the treatment of hypertension and cardiovascular disorders [ 53 ].
In addition, 1,4-DHP class of compounds is excellent synthon for the development of antitubercular agents [ 54 — 56 ]. In continuation of search for 1,4-DHPs with improved antitubercular activity, Gaveriya et al. The diaryls were synthesized by condensation of 4,5-dichloroimidazolecarboxaldehyde 18N-aryl acetoacetamide 19and ammonium acetate in methanol.
Synthesis of pyridine dicarboxamides. They tested all compounds against M. The antitubercular activity result indicated that the substitution of 4,5-dichloroimidazole ring at 4-position of 1,4-DHP affects the antitubercular activity when 3,5-diester group in classic DHP structure was replaced by carboxamide moiety. On comparison, the most active compound is 20d with 3-chlorophenyl group at 3,5-dicarboxamide position. Although none of the new compounds had antibacterial activity comparable with rifampicin, the results serve as valuable probes to study the structure function relationship for antitubercular activity.
Synthesis of Novel Thiadiazolyl Pyrrolidine Carboxamides A new direction in the synthesis of antitubercular agents is directed on the design of molecules acting as enzyme inhibitors. The target enzyme should play a vital role in any phase of the life cycle of the pathogen and should be absent in the host. Enoyl-acyl carrier protein reductase is a FAS II enzyme involved in the bacterial fatty acid biosynthetic pathway in the mycobacterium and other bacteria [ 61 ].
These enzymes are involved in fatty acid elongation in the cell wall synthesis. The prime TB drug isoniazid is reported to be a potent enoyl-ACP reductase inhibitor but requires initial activation by Kat G, a catalase peroxidase enzyme [ 62 ].
This activation step necessitated the search for new antitubercular agents which can act as direct enoyl ACP reductase inhibitors. This prompted Boyne et al. In their synthesis, 5-oxophenylpyrrolidinecarboxylic acid 23 was synthesized by refluxing a mixture of itaconic acid , aniline , and water for 1 h or until the odour of aniline becomes faint after which the reaction was chilled for 1 h. The synthesis of 2-amino 4-substituted phenyl aryl-1,3,4-thiadiazole 25 was achieved by dissolving aromatic aldehyde and thiosemicarbazide, respectively, in warm alcohol and warm water and mixing the two solutions slowly with stirring.
The target compounds were synthesized by dissolving compounds 23 and 25 in dry DMF. The reaction was quenched using NaCl solution and the mixture extracted with ethyl acetate. The combined ethyl acetate layer was washed with 1N HCl and then with saturated sodium bicarbonate followed by brine Scheme 5. Synthesis of thiazolyl pyrrolidine carboxamides. The antimycobacterial activities of the compounds were assessed against M. The antitubercular activities are as presented in Table 2.
Synthesis of Substituted N-Phenylmethyloxophenyl-1,2,3,4-tetrahydro Pyrimidinecarboxamides Within the pyrimidines, 2,4-diaminopyrimidines have been reported to have IC50 of 0. The most effective derivative in the chloropyrimidine series has an MIC of 0. The most effective inhibitor of this class has a Ki of These results prompted Vanheusden et al. Compounds 29a—n were synthesized by reacting substituted amines and ethyl acetoacetate in toluene with a catalytic amount of NaOH or KOH Scheme 6.
Acetoacetanilides, thus obtained, were used as 1,3-diketone adducts for the multicomponent Biginelli reaction. Synthesis of pyrimidine carboxamides. The acetoacetanilides 29a—n were reacted with substituted aldehydes and urea in methanol using concentrated HCl in catalytic amount to obtain the title compounds 31a—v, 32a—g as depicted in Scheme 6. The antitubercular activities of the compounds were tested against M.
Percentage inhibition data of compounds 31a—v, 32a—g are reported in Table 3. Thus, methyl group at these positions showed higher potency. But substitutions on 4-phenyl ring also alter the activity of compound. Thus, compounds with methyl substitution on phenyl carbamoyl side chain with —OPh or —NO2 substitution at meta-position of 4-phenyl ring were more potent than the same substitution on para-position.
The replacement of methyl group in phenyl ring of phenyl carbamoyl side chain with halogens results in the loss of antitubercular activity. Compounds with halogen substituted at different positions of phenyl ring of phenyl carbamoyl side chain do not show good potency either with meta- or with para-substituted 4-phenyl ring of C5 side chain with meta-substituted 4-phenyl ring showing good potency. Synthesis of Aryl Thiazolidine Carboxamides Sriram et al.
The compounds were synthesized from 2- substituted aryl -N- substituted thiazolidinecarboxamides 34a—d. Potassium acetate was added to a solution of L-cysteine hydrochloride 33 in water. To this homogenous mixture, ethanol and appropriate aldehyde 30 were added. The solid that precipitated was filtered and washed with cold ethanol and dried to afford 34a—d.
To this mixture, appropriate primary or secondary amine was added and stirred for 8 h. The solid urea separated was filtered off and the organic layer was washed with water and dried over sodium sulphate and distilled under reduced pressure to yield the desired product Scheme 7.
Synthesis of aryl thiazolidine carboxamides. The compounds were screened for their in vitro antimycobacterial activity against M. The result of the MIC is as given in Table 4. For the 5-nitroimidazoles, neither the corresponding bicyclic analog, nor addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazo-oxazine provided the first 5-nitroimidazole with aerobic activity.
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Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase Ddn retained anaerobic sensitivity to some compounds.
Aerobic activity appears to be correlated with efficiency as a substrate for Ddn, suggesting a means of structure-based optimization of improved nitroimidazoles.
Introduction Tuberculosis, caused by Mycobacterium tuberculosis Mtb acontinues to be a major threat to global public health, killing more than 1. The nitroimidazoles, such as S nitro 4- trifluoromethoxy benzyloxy -6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine PA, 1 5are a promising new class of compounds that have shown antitubercular activity under hypoxic conditions and are currently in clinical evaluation. Metronidazole Mtz, 2- 2-methylnitro-1H-imidazolyl ethanol, 2a 5-nitroimidazole, is widely used for the treatment of diseases caused by anaerobic bacteria.
A better understanding of the SAR would help us to determine if these diverse groups of nitroimidazole compounds have the same cellular mode of action. In particular, we were interested in the differences or similarities in SAR between the 4-nitroimidazo-oxazines typified by PA and the 5-nitroimidazoles such as Mtzand additionally whether the SAR for the aerobic activity would mirror that of the anaerobic activity.
To simplify the discussion, we will use the numbering for the imidazole ring throughout the paper. Thus, Mtz has a 5-nitro substituent, while PA and compound 3 are referred to as 4-nitro derivatives. Chemistry Simple comparison of the structures of Mtz and PA revealed four key differences: